Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (gnrh) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer

ABSTRACT

The invention relates to a group of novel pyrazole compounds of Formula (I): wherein: R 1 , R 2 , R 3 , M and R 5  are as defined in the specification, which are useful as gonadotrophin releasing hormone antagonists. The invention also relates to pharmaceutical formulations of said compounds, methods of treatment using said compounds and to processes for the preparation of said compounds.

The present invention relates to compounds which are antagonists of gonadotropin releasing hormone (GnRH) activity. The invention also relates to pharmaceutical formulations, the use of a compound of the present invention in the manufacture of a medicament, a method of therapeutic treatment using such a compound and processes for producing the compounds.

Gonadotropin releasing hormone (GnRH) is a decapeptide that is secreted by the hypothalamus into the hypophyseal portal circulation in response to neural and/or chemical stimuli, causing the biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary. GnRH is also known by other names, including gonadoliberin, LH releasing hormone (LHRH), FSH releasing hormone (FSH RH) and LH/FSH releasing factor (LH/FSH RF).

GnRH plays an important role in regulating the action of LH and FSH (by regulation of their levels), and thus has a role in regulating the levels of gonadal steroids in both sexes, including the sex hormones progesterone, oestrogens and androgens. More discussion of GnRH can be found in WO 98/5519 and WO 97/14697, the disclosures of which are incorporated herein by reference.

It is believed that several diseases would benefit from the regulation of GnRH activity, in particular by antagonising such activity. These include sex hormone related conditions such as sex hormone dependent cancer, benign prostatic hypertrophy and myoma of the uterus. Examples of sex hormone dependent cancers are prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenoma.

The following disclose compounds purported to act as GnRH antagonists: WO 97/21435, WO 97/21703, WO 97/21704, WO 97/21707, WO 55116, WO 98/55119, WO 98/55123, WO 98/55470, WO 98/55479, WO 99/21553, WO 99/21557, WO 99/41251, WO 99/41252, WO 00/04013, WO 00/69433, WO 99/51231, WO 99/51232, WO 99/51233, WO 99/51234, WO 99/51595, WO 99/51596, WO 00/53178, WO 00/53180, WO 00/53179, WO 00/53181, WO 00/53185, WO 00/53602, WO 02/066477, WO 02/066478, WO 02/06645 and WO 02/092565.

It would be desirable to provide further compounds, such compounds being GnRH antagonists. Thus, according to the first aspect of the invention there is provided a compound of Formula (I),

wherein:

-   -   R¹ is selected from: hydrogen, optionally-substituted C₁₋₆alkyl,         optionally substituted aryl or optionally-substituted         arylC₁₋₆alkyl;     -   R² is an optionally-substituted mono or bi-cyclic aromatic ring;     -   R³ is selected from a group of Formula (IIa) to Formula (IIf):     -   R⁵ is a group of Formula (III):     -   R⁶ and R^(6a) are independently selected from hydrogen, fluoro,         optionally substituted C₁₋₆alkyl, optionally-substituted aryl or         optionally substituted arylC₁₋₆alkyl, or R⁶ and R^(6a) taken         together and the carbon atom to which they are attached form a         carbocyclic ring of 3-7 atoms, or R⁶ and R^(6a) taken together         and the carbon atom to which they are attached form a carbonyl         group;     -   or when A is not a direct bond the group     -    forms a carbocyclic ring of 3-7 carbon atoms or a heterocyclic         ring containing one or more heteroatoms;     -   or the group     -    forms a heterocyclic ring containing 3-7 carbon atoms and one         or more heteroatoms;     -   R⁷ is selected from: hydrogen, optionally-substituted C₁₋₆alkyl,         optionally-substituted arylC₁₋₆alkyl, optionally-substituted         aryl, optionally substituted heterocyclyl, optionally         substituted heterocyclylC₁₋₆alkyl, R⁹OC₁₋₆alkyl-,         R⁹R¹⁰NC₁₋₆alkyl-, R⁹R¹⁰NC(O)C₁₋₆alkyl, —C(NR⁹R¹⁰)═NH;         -   or when R³ is a group of Formula (IIc) or (IId) R⁷ is of the             formula -J-K—R⁸;     -   R⁸ is selected from:         -   (i) hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,             haloC₁₋₆alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxy,             hydroxyC₁₋₆alkyl, cyano, N—C₁₋₄alkylamino,             N,N-di-C₁₋₄alkylamino, C₁₋₆alkyl-S(O_(n))—, —O—R^(b),             —NR^(b)R^(c), —C(O)—R^(b), —C(O)O—R^(b), —CONR^(b)R^(c),             NH—C(O)—R^(b) or —S(O_(n))NR^(b)R^(c),             -   where R^(b) and R^(c) are independently selected from                 hydrogen and C₁₋₄alkyl optionally substituted with                 hydroxy, amino, N—C₁₋₄alkylamino, N,N-di-C₁₋₄alkylamino,                 HO—C₂₋₄alkyl-NH— or HO—C₂₋₄alkyl-N(C₁₋₄alkyl)-;         -   (ii) nitro when B is a group of Formula (IV) and X is CH and             p is 0;         -   (iii) C₃₋₇cycloalkyl, aryl or arylC₁₋₆alkyl each of which is             optionally substituted by R¹², R¹³ and R¹⁴;         -   (iv) -(Q)-aryl, -(Q)-heterocyclyl, -aryl-(Q)-aryl, each of             which is optionally substituted by R¹², R¹³ and R¹⁴             -   wherein -(Q)- is selected from E, F or a direct bond;         -   (v) heterocyclyl or heterocyclylC₁₋₆alkyl each of which is             optionally substituted by up to 4 substituents independently             selected from R¹², R¹³ and R¹⁴;         -   (vi) a group selected from R¹², R¹³ and R¹⁴;     -   R⁹ and R¹⁰ are independently selected from: hydrogen, hydroxy,         optionally substituted C₁₋₆alkyl, optionally substituted aryl,         optionally substituted arylC₁₋₆alkyl, an optionally substituted         carbocyclic ring of 3-7 atoms, optionally substituted         heterocyclyl, optionally substituted heterocyclylC₁₋₆alkyl or R⁹         and R¹⁰ taken together can form an optionally substituted ring         of 3-9 atoms or R⁹ and R¹⁰ taken together with the carbon atom         to which they are attached form a carbonyl group;     -   R¹¹ is selected from: hydrogen, optionally substituted         C₁₋₆alkyl, or N(R⁹R¹⁰);     -   R¹² is selected from: hydrogen, hydroxy, R¹⁷R¹⁸N(CH₂)_(cc)—,         R¹⁷R¹⁸NC(O)(CH₂)_(cc)—, optionally substituted         C₁₋₆alkyl-C(O)N(R⁹)(CH₂)_(cc)—, optionally substituted         C₁₋₆alkyl-SO₂N(R⁹)—, optionally substituted aryl-SO₂N(R⁹)—,         C₁₋₃perfluoroalkyl-SO₂N(R⁹)—; optionally substituted         C₁₋₆alkyl-N(R⁹)SO₂—, optionally substituted aryl-N(R⁹)SO₂—,         C₁₋₃perfluoroalkyl-N(R⁹)SO₂—, optionally substituted         C₁₋₆alkanoyl-N(R⁹)SO₂—; optionally substituted         aryl-C(O)N(R⁹)SO₂—, optionally substituted C₁₋₆alkyl-S(O_(n))—,         optionally substituted aryl-S(O_(n))—, C₁₋₃perfluoroalkyl-,         C₁₋₃perfluoroalkoxy, optionally substituted C₁₋₆alkoxy, carboxy,         halo, nitro or cyano;     -   R¹³ and R¹⁴ are independently selected from: hydrogen, hydroxy,         oxo, optionally substituted C₁₋₆alkyl, optionally substituted         C₁₋₆alkanoyl, optionally substituted C₂₋₆alkenyl, cyano, nitro,         C₁₋₃perfluoroalkyl-, C₁₋₃perfluoroalkoxy, optionally substituted         aryl, optionally substituted arylC₁₋₆alkyl, R⁹O(CH₂)_(s)—,         R⁹(O)O(CH₂)_(s)—, R⁹OC(O)(CH₂)_(s)—, R¹⁶S(O_(n))(CH₂)_(s)—,         R⁹R¹⁰NC(O)(CH₂)_(s)— or halo;     -   R¹⁵ is selected from: hydrogen, optionally substituted         C₁₋₆alkyl, R¹⁹OC(O)—, R⁹R¹⁰NC(O)—, R⁹C(O)—, R⁹S(O_(n))—;     -   R¹⁶ is selected from: hydrogen, C₁₋₆alkyl, C₁₋₃perfluoroalkyl or         optionally-substituted aryl;     -   R¹⁷ is independently selected from: hydrogen, hydroxy, cyano or         optionally substituted C₁₋₆alkyl;     -   R¹⁸ is a group of formula R^(18a)—C(R⁹R¹⁰)₀₋₁— wherein R^(18a)         is selected from: R¹⁹OC(O)—, R⁹R¹⁰NC(O)—, R⁹R¹⁰N—, R⁹C(O)—,         R⁹C(O)N(R¹⁰)—, R⁹R¹⁰NC(O)—, R⁹R¹⁰NC(O)N(R¹⁰)—, R⁹SO₂N(R¹⁰)—,         R⁹R¹⁰NSO₂N(R¹⁰)—, R⁹C(O)O—, R⁹OC(O)—, R⁹R¹⁰NC(O)O—, R⁹O—,         R⁹S(O_(n))—, R⁹R¹⁰NS(O_(n))—, hydrogen, optionally substituted         C₁₋₆alkyl, optionally substituted heterocyclyl;     -   or R¹⁷ and R¹⁸ when taken together form an optionally         substituted carbocyclic ring of 3-7 atoms or optionally         substituted heterocyclyl;     -   R¹⁹ is selected from: hydrogen, optionally substituted C₁₋₆alky,         optionally substituted aryl, optionally substituted         arylC₁₋₆alkyl, optionally substituted C₃₋₇cycloalkyl, optionally         substituted heterocyclyl or optionally substituted         heterocyclylC₁₋₆alkyl;     -   R²¹ and R²² are independently selected from hydrogen, optionally         substituted C₁₋₆alkyl, optionally substituted C₃₋₇cycloalkyl,         optionally substituted heterocyclyl, optionally substituted         heterocyclylC₁₋₆alkyl, optionally substituted C₃₋₆alkenyl,         optionally substituted C₃₋₆alkynyl,         —(C₁₋₅alkyl)_(aa)-S(O_(n))—(C₁₋₅alkyl)_(bb)-; R⁹R¹⁰NC₂₋₆alkyl,         R⁹OC₂₋₆alkyl or R⁹R¹⁰NC(O)C₂₋₆alkyl, with the proviso that R⁹         and R¹⁰ independently or taken together are not optionally         substituted aryl or optionally substituted arylC₁₋₆alkyl; or     -   R²¹ and R²² taken together form an optionally substituted         non-aromatic heterocyclic ring;     -   A is selected from:         -   (i) a direct bond;         -   (ii) optionally-substituted C₁₋₅alkylene wherein the             optional substituents are independently selected from:             optionally-substituted C₁₋₆-alkyl optionally-substituted             aryl or optionally substituted arylC₁₋₆alkyl;         -   (iii) a carbocyclic ring of 3-7 atoms;         -   (iv) a carbonyl group or —C(O)—C(R^(d)R^(d))—, wherein R^(d)             is independently selected from hydrogen and C₁₋₂alkyl;     -   or when R³ is a group of Formula (IIa) or (IIb), the group     -    forms a heterocyclic ring containing 3-7 carbon atoms and one         or more heteroatoms;     -   or when R³ is a group of Formula (IIa), (IIb), (IIc) or (IId),         the group     -    forms a heterocyclic ring containing 3-7 carbon atoms and one         or more heteroatoms;     -   B is selected from:         -   (i) a direct bond;         -   (ii) a group of Formula (IV)             -   wherein:             -   X is selected from N or CH,                 -   wherein at position (a) Formula (IV) is attached to                     the nitrogen atom and the (CH₂)_(p) group is                     attached to R⁸; and         -   (iii) a group independently selected from: optionally             substituted C₁₋₆alkylene, optionally substitute             C₃₋₇cycloalkyl, optionally substituted C₃₋₆alkenylene,             optionally substituted C₃₋₆alkynyl, C₁₋₆alkoxy,             (C₁₋₅alkyl)_(aa)-S(O_(n))—(C₁₋₅alkyl)_(bb)-,             —(C₁₋₅alkyl)_(aa)-O—(C₁₋₅alkyl)_(bb)-,             —(C₁₋₅alkyl)_(aa)-C(O)—(C₁₋₅alkyl)_(bb)- or             (C₁₋₅alkyl)_(aa)-N(R¹⁵)—(C₁₋₅alkyl)_(bb),             -   wherein R¹⁵ and the (C₁₋₅alkyl)_(aa) or (C₁₋₅alkyl)_(bb)                 chain can be joined to form a ring, wherein the combined                 length of (C₁₋₅alkyl)_(aa) and (C₁₋₅alkyl)_(bb) is less                 than or equal to C₅alkyl;     -   or the group —B—R⁸ represents a group of Formula (V)     -   or the group     -    together forms an optionally substituted heterocyclic ring         containing 4-7 carbons atoms;     -   or the group     -    forms a heterocyclic ring containing 3-7 carbon atoms and one         or more heteroatoms;     -   E is —O—, —S(O_(n)), —C(O)—, —NR¹⁵— or —C(R⁹R¹⁰)_(q);     -   F is -E(CH₂)_(r)—;     -   G is selected from: hydrogen, halo, N, O, S(O_(n)), C(O),         C(R⁹R¹⁰)_(t), optionally substituted C₂₋₆alkenylene, optionally         substituted C₂₋₆alkynylene or a direct bond to R¹⁸,     -   J is a group of the formula: —(CH₂)_(s)-L-(CH₂)_(s)— wherein         when s is greater than 0, the alkylene group is optionally         substituted,     -   or the group     -    together forms an optionally substituted heterocyclic ring         containing 4-7 carbons atoms;     -   K is selected from: a direct bond, —(CH₂)_(s1)—,         —(CH₂)_(s1)—O—(CH₂)_(s2)—, —(CH₂)_(s1)—C(O)—(CH₂)_(s2)—,         —(CH₂)_(s1)—S(O_(n))—(CH₂)_(s2)—,         —(CH₂)_(s1)—N(R¹⁸)—(CH₂)_(s2)—,         —(CH₂)_(s1)—C(O)N(R⁹)—(CH₂)_(s2)—, —(CH₂)_(s1),         —N(R⁹)C(O)—(CH₂)_(s2)—, —(CH₂)_(s1)—N(R⁹)C(O)N(R⁹)—(CH₂)_(s2)—,         —(CH₂)_(s1)—OC(O)—(CH₂)_(s2)—, —(CH₂)_(s1)—C(O)O—(CH₂)_(s2)—,         —(CH₂)_(s1)—N(R⁹)C(O)O—(CH₂)_(s2)—,         —(CH₂)_(s1)—OC(O)N(R⁹)—(CH₂)_(s2)—,         —(CH₂)_(s1)—OS(O_(n))—(CH₂)_(s2)—, or         —(CH₂)_(s1)—S(O_(n))—O—(CH₂)_(s2)—,         —(CH₂)_(s1)—S(O)₂N(R⁹)—(CH₂)_(s2)— or         —(CH₂)_(s1)—N(R⁹)S(O)₂—(CH₂)_(s2)—; wherein the —(CH₂)_(s1)— and         —(CH₂)_(s2)— groups are independently optionally substituted by         hydroxy or C₁₋₄alkyl;     -   L is selected from optionally substituted aryl or optionally         substituted heterocyclyl;     -   M is selected from —(CH₂)₀₋₂—O— or C(O)NH—;     -   n is an integer from 0 to 2;     -   p is an integer from 0 to 4;     -   q is an integer from 0 to 4;     -   r is an integer from 0 to 4;     -   s is an integer from 0 to 4;     -   s1 and s2 are independently selected from an integer from 0 to         4, and s1+s2 is less than or equal to 4;     -   t is an integer between 0 and 4; and     -   aa and bb are independently 0 or 1;     -   cc is an integer between 0 to 2;     -   with the proviso that     -   (i) when G is hydrogen or halo, then R¹⁷ and R¹⁸ are both         absent;     -   (ii) when G is O, S(O_(n)), C(O) or C(R¹¹R¹²)_(t) then G is         substituted by a single group independently selected from the         definition of R¹⁷ or R¹⁸ and when G is a direct bond to R¹⁸ then         G is substituted by a single group selected from R¹⁸;     -   (iii) when R³ is a group of Formula (IIb), B is a group of         Formula (IV), R⁸ is selected from group (i) or (ii) above, R¹¹         is a group of the formula N(R¹⁰R¹¹) and R¹, R² and R⁵ are as         defined above then R⁴ cannot be hydrogen;     -   (iv) R³ cannot be unsubstituted pyridyl or unsubstituted         pyrimidinyl; and     -   (v) when R³ is pyrazolyl substituted by phenyl or pyrazolyl         substituted by phenyl and acetyl, R⁵-M is hydroxyl or acetyloxy,         R² is unsubstituted phenyl, then R¹ cannot be hydrogen or         acetyl;     -   or a salt, solvate or pro-drug thereof.

According to the further feature of the first aspect of the invention there is provided a compound of Formula (I) with the proviso that

-   -   (i) when G is hydrogen or halo, then R¹⁷ and R¹⁸ are both         absent;     -   (ii) when G is O, S(O_(n)), C(O) or C(R¹¹R¹²)_(t) then G is         substituted by a single group independently selected from the         definition of R¹⁷ or R¹⁸ and when G is a direct bond to R¹⁸ then         G is substituted by a single group selected from R¹⁸;     -   (iii) when R³ is a group of Formula (IIb), B is a group of         Formula (IV), R⁸ is selected from group (i) or (ii) above, R¹¹         is a group of the formula N(R¹⁰R¹¹) and R¹, R² and R⁵ are as         defined above then R⁴ cannot be hydrogen; and     -   (iv) R³ cannot be an unsubstituted or substituted aromatic         heterocyclic ring, wherein the aromatic heterocyclic ring is         attached directed to the pyrazole in Formula (I);     -   or a salt, solvate or pro-drug thereof.

According to the further feature of the first aspect of the invention there is provided a compound of Formula (Ia),

wherein:

-   -   R¹ is selected from: hydrogen, optionally-substituted C₁₋₆alkyl,         optionally substituted aryl or optionally-substituted         arylC₁₋₆alkyl;     -   R² is an optionally-substituted mono or bi-cyclic aromatic ring;     -   R³ is selected from a group of Formula (IIa) to Formula (IIf):     -   R⁵ is a group of Formula (III):     -   R⁶ and R^(6a) are independently selected from hydrogen,         optionally substituted C₁₋₆alkyl, optionally-substituted aryl or         optionally substituted arylC₁₋₆alkyl, or R⁶ and R^(6a) taken         together and the carbon atom to which they are attached form a         carbocyclic ring of 3-7 atoms, or R⁶ and R^(6a) taken together         and the carbon atom to which they are attached form a carbonyl         group;     -   or when A is not a direct bond the group     -    forms a carbocyclic ring of 3-7 carbon atoms or a heterocyclic         ring containing one or more heteroatoms;     -   or the group     -    forms a heterocyclic ring containing 3-7 carbon atoms and one         or more heteroatoms;     -   R⁷ is selected from: hydrogen, optionally-substituted C₁₋₆alkyl,         optionally-substituted arylC₁₋₆alkyl, optionally-substituted         aryl, optionally substituted heterocyclyl, optionally         substituted heterocyclylC₁₋₆alkyl, R⁹OC₁₋₆alkyl-,         R⁹R¹⁰NC₁₋₆alkyl-, R⁹R¹⁰NC(O)C₁₋₆alkyl, —C(NR⁹R¹⁰)═NH;         -   or when R³ is a group of Formula (IIc) or (IId) R⁷ is of the             formula -J-K—R⁸;     -   R⁸ is selected from:         -   (i) hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,             haloC₁₋₆alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxy,             hydroxyC₁₋₆alkyl, cyano, N—C₁₋₄alkylamino,             N,N-di-C₁₋₄alkylamino, C₁₋₆alkyl-S(O_(n))—, —O—R^(b),             —NR^(b)R^(c), —C(O)—R^(b), —C(O)O—R^(b), —CONR^(b)R^(c) or             NH—C(O)—R^(b),             -   where R^(b) and R^(c) are independently selected from                 hydrogen and C₁₋₄alkyl optionally substituted with                 hydroxy, amino, N—C₁₋₄alkylamino, N,N-di-C₁₋₄alkylamino,                 HO—C₂₋₄alkyl-NH— or HO—C₂₋₄alkyl-N(C₁₋₄alkyl)-;         -   (ii) nitro when B is a group of Formula (IV) and X is CH and             p is 0;         -   (iii) C₃₋₇cycloalkyl, aryl or arylC₁₋₆-alkyl each of which             is optionally substituted by R¹², R¹³ and R¹⁴;         -   (iv) -(Q)-aryl, -(Q)-heterocyclyl, -aryl-(Q)-aryl, each of             which is optionally substituted by R¹², R¹³ and R¹⁴             -   wherein -(Q)- is selected from E, F or a direct bond;         -   (v) heterocyclyl or heterocyclylC₁₋₆alkyl each of which is             optionally substituted by R¹², R¹³ and R¹⁴;         -   (vi) a group selected from R¹², R¹³ and R¹⁴;     -   R⁹ and R¹⁰ are independently selected from: hydrogen, hydroxy,         optionally substituted C₁₋₆alkyl, optionally substituted aryl,         optionally substituted arylC₁₋₆alkyl, an optionally substituted         carbocyclic ring of 3-7 atoms, optionally substituted         heterocyclyl, optionally substituted heterocyclylC₁₋₆alkyl or R⁹         and R¹⁰ taken together can form an optionally substituted ring         of 3-9 atoms or R⁹ and R¹⁰ taken together with the carbon atom         to which they are attached form a carbonyl group;     -   R¹¹ is selected from: hydrogen, optionally substituted         C₁₋₆alkyl, or N(R⁹R¹⁰);     -   R¹² is selected from: hydrogen, hydroxy, R¹⁷R¹⁸N—, optionally         substituted C₁₋₆alkyl-SO₂N(R⁹)—, optionally substituted         aryl-SO₂N(R⁹)—, C₁₋₃perfluoroalkyl-SO₂N(R⁹)—; optionally         substituted C₁₋₆alkyl-N(R⁹)SO₂—, optionally substituted         aryl-N(R⁹)SO₂—, C₁₋₃perfluoroalkyl-N(R⁹)SO₂— optionally         substituted C₁₋₆alkanoyl-N(R⁹)SO₂—; optionally substituted         aryl-C(O)N(R⁹)SO₂, optionally substituted C₁₋₆alkyl-S(O_(n))—,         optionally substituted aryl-S(O_(n))—, C₁₋₃perfluoroalkyl-,         C₁₋₃perfluoroalkoxy, optionally substituted C₁₋₆alkoxy, carboxy,         halo, nitro or cyano;     -   R¹³ and R¹⁴ are independently selected from: hydrogen,         optionally substituted C₁₋₆alkyl, optionally substituted         C₂₋₆alkenyl, cyano, nitro, C₁₋₃perfluoroalkyl-,         C₁₋₃perfluoroalkoxy, optionally substituted aryl, optionally         substituted arylC₁₋₆alkyl, R⁹O(CH₂)_(s)—, R⁹(O)O(CH₂)_(s)—,         R⁹OC(O)(CH₂)_(s)—, R¹⁶S(O_(n))(CH₂)_(s)—, R⁹R¹⁰NC(O)(CH₂)_(s)—         or halo;     -   R¹⁵ is selected from: hydrogen, optionally substituted         C₁₋₆alkyl, R¹⁹OC(O)—, R⁹R¹⁰NC(O)—, R⁹C(O)—, R⁹S(O_(n))—;     -   R¹⁶ is selected from: hydrogen, C₁₋₆alkyl, C₁₋₃perfluoroalkyl or         optionally-substituted aryl;     -   R¹⁷ is independently selected from: hydrogen, hydroxy, cyano or         optionally substituted C₁₋₆alkyl;     -   R¹⁸ is a group of formula R^(18a)—C(R⁹R¹⁰)₀₋₁— wherein R^(18a)         is selected from: R¹⁹OC(O)—, R⁹R¹⁰NC(O)—, R⁹R¹⁰N—, R⁹C(O)—,         R⁹C(O)N(R¹⁰)—, R⁹R¹⁰NC(O)—, R⁹R¹⁰NC(O)N(R¹⁰)—, R⁹SO₂N(R¹⁰)—,         R⁹R¹⁰NSO₂N(R¹⁰)—, R⁹C(O)O—, R⁹OC(O)—, R⁹R¹⁰NC(O)O—, R⁹O—,         R⁹S(O_(n))—, R⁹R¹⁰NS(O_(n))—, optionally substituted C₁₋₆alkyl,         optionally substituted heterocyclyl;     -   or R¹⁷ and R¹⁸ when taken together form an optionally         substituted carbocyclic ring of 3-7 atoms or optionally         substituted heterocyclyl;     -   R¹⁹ is selected from: hydrogen, optionally substituted C₁₋₆alky,         optionally substituted aryl, optionally substituted         arylC₁₋₆alkyl, optionally substituted C₃₋₇cycloalkyl, optionally         substituted heterocyclyl or optionally substituted         heterocyclylC₁₋₆alkyl;     -   R²⁰ is selected from R¹² or R¹³;     -   R²¹ and R²² are independently selected from hydrogen, optionally         substituted C₁₋₆alkyl, optionally substituted C₃₋₇cycloalkyl,         optionally substituted heterocyclyl, optionally substituted         heterocyclylC₁₋₆alkyl, optionally substituted C₃₋₆alkenyl,         optionally substituted C₃₋₆alkynyl,         —(C₁₋₅alkyl)_(aa)-S(O_(n))—(C₁₋₅alkyl)_(bb)-; R⁹R¹⁰NC₂₋₆alkyl,         R⁹OC₂₋₆alkyl or R⁹R¹⁰NC(O)C₂₋₆alkyl, with the proviso that R⁹         and R¹⁰ independently or taken together are not optionally         substituted aryl or optionally substituted arylC₁₋₆alkyl; or     -   R²¹ and R²² taken together form an optionally substituted         non-aromatic heterocyclic ring;     -   A is selected from:         -   (i) a direct bond;         -   (ii) optionally-substituted C₁₋₅alkylene wherein the             optional substituents are independently selected from:             optionally-substituted C₁₋₆alkyl optionally-substituted             aryl, optionally substituted arylC₁₋₆alkyl or substituted         -   (iii) a carbocyclic ring of 3-7 atoms;         -   (iv) a carbonyl group;     -   or when R³ is a group of Formula (IIa) or (IIb), the group     -    forms a heterocyclic ring containing 3-7 carbon atoms and one         or more heteroatoms;     -   or when R³ is a group of Formula (IIa), (IIb), (IIc) or (IId),         the group     -    forms a heterocyclic ring containing 3-7 carbon atoms and one         or more heteroatoms;     -   B is selected from:         -   (i) a direct bond;         -   (ii) a group of Formula (IV)         -   wherein:         -   X is selected from N or CH,             -   wherein at position (a) Formula (IV) is attached to the                 nitrogen atom and the (CH₂)p group is attached to R⁸;                 and         -   (iii) a group independently selected from: optionally             substituted C₁₋₆alkylene, optionally substitute             C₃₋₇cycloalkyl, optionally substituted C₃₋₆alkenylene,             optionally substituted C₃₋₆alkyl, C₁₋₆alkoxy,             (C₁₋₅alkyl)_(aa)-S(O_(n))—(C₁₋₅alkyl)_(bb)-,             (C₁₋₅alkyl)_(aa)-O—(C₁₋₅alkyl)_(bb)- or             (C₁₋₅alkyl)_(aa)-N(R¹⁵)—(C₁₋₅alkyl)_(bb),             -   wherein R¹⁵ and the (C₁₋₅alkyl)_(aa) or (C₁₋₅alkyl)_(bb)                 chain can be joined to form a ring;     -   or the group —B—R⁸ represents a group of Formula (V)     -   or the group     -    together forms a heterocyclic ring containing 5-7 carbons         atoms;     -   or the group     -    forms a heterocyclic ring containing 3-7 carbon atoms and one         or more heteroatoms;     -   E is —O—, —S(O_(n)), —C(O)—, —NR¹⁵— or —C(R⁹R¹⁰)_(q);     -   F is -E(CH₂)_(r)—;     -   G is selected from: hydrogen, halo, N, O, S(O_(n)), C(O),         C(R⁹R¹⁰)_(t), optionally substituted C₂₋₆alkenylene, optionally         substituted C₂₋₆alkynylene or a direct bond to R¹⁸,     -   J is a group of the formula: —(CH₂)_(s)-L-(CH₂)_(s)— wherein         when s is greater than 0, the alkylene group is optionally         substituted     -   K is selected from: a direct bond, —O—(CH₂)_(s)—,         —C(O)—(CH₂)_(s)—, —S(O_(n))—(CH₂)_(s)—, —N(R¹⁸)—(CH₂)_(s)—,         —OC(O)—(CH₂)_(s)—, —C(O)O—(CH₂)_(s)—, —OS(O_(n))—(CH₂)_(s)—, or         —S(O_(n))—O—(CH₂)_(s)—;     -   L is selected from optionally substituted aryl or optionally         substituted heterocyclyl;     -   M is —(CH₂)₀₋₂—O—;     -   n is an integer between 0 and 2;     -   p is an integer between 0 and 4;     -   q is an integer between 0 and 4;     -   r is an integer between 0 and 4;     -   s is an integer between 0 and 4; and     -   t is an integer between 0 and 4;     -   with the proviso that         -   (i) when G is hydrogen or halo, then R¹⁷ and R¹⁸ are both             absent;         -   (ii) when G is O, S(O_(n)), C(O) or C(R¹¹R¹²)_(t) then G is             substituted by a single group independently selected from             the definition of R¹⁷ or R¹⁸ and when G is a direct bond to             R¹⁸ then G is substituted by a single group selected from             R¹⁸; and     -   or a salt, solvate or pro-drug thereof.

According to a further feature of the first aspect of the invention there is provided a pharmaceutical formulation comprising a compound of Formula (I) or Formula (Ia), or salt, pro-drug or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

According to a further feature of the first aspect of the invention there is provided the following uses of a compound of Formula (I) or Formula (Ia), or salt, pro-drug or solvate thereof:

-   (a) the use in the manufacture of a medicament for antagonising     gonadotropin releasing hormone activity; -   (b) the use in the manufacture of a medicament for administration to     a patient, for reducing the secretion of luteinizing hormone by the     pituitary gland of the patient; and -   (c) the use in the manufacture of a medicament for administration to     a patient, for therapeutically treating and/or preventing a sex     hormone related condition in the patient, preferably a sex hormone     related condition selected from prostate cancer and pre-menopausal     breast cancer.

According to a further aspect of the invention there is provided a method of antagonising gonadotropin releasing hormone activity in a patient, comprising administering a compound of Formula (I) or Formula (Ia), or salt, pro-drug or solvate thereof, to a patient.

Whilst pharmaceutically-acceptable salts of compounds of the invention are preferred, other non-pharmaceutically-acceptable salts of compounds of the invention may also be useful, for example in the preparation of pharmaceutically-acceptable salts of compounds of the invention.

Whilst the invention comprises compounds of the invention, and salts, pro-drugs or solvates thereof, in a further embodiment of the invention, the invention comprises compounds of the invention and salts thereof.

In the present specification, unless otherwise indicated, an alkyl, alkylene, alkenyl or alkynyl moiety may be linear or branched. The term “alkylene” refers to the group —CH₂—. Thus, C₈ alkylene for example is —(CH)₈—. For avoidance of doubt the term C₀alkyl within the group C₀₋₅alkyl is a direct bond.

The term ‘propylene’ refers to trimethylene and the branched alkyl chains —CH(CH₃)CH₂— and —CH₂—CH(CH₃)—. The straight chain propylene di-radical is preferred, i.e. —CH₂CH₂CH₂—. Specific propylene radicals refer to the particular structure, thus the term, propyl-2-ene refers to the group —CH₂—CH(CH₃)—. Similar notation is used for other divalent alkyl chains such as butylene.

The term ‘2-propenyl’ refers to the group —CH₂—CH═CH—.

The term “aryl” refers to phenyl or naphthyl.

The term “carbamoyl” refers to the group —C(O)NH₂.

The term “halo” refers to fluoro, chloro, bromo or iodo.

The term “heterocyclyl” or “heterocyclic ring” refers to a 4-12 membered, preferably 5-10 membered aromatic mono or bicyclic ring or a 4-12 membered, preferably 5-10 membered saturated or partially saturated mono or bicyclic ring, said aromatic, saturated or partially unsaturated rings containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1-nitrogen of a pyrazole ring. Examples of 5- or 6-membered aromatic heterocyclic rings include pyrrolyl, furanyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl and thienyl. A 9 or 10 membered bicyclic aromatic heterocyclic ring is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuranyl, benzimidazolyl, benzthiophenyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, indolyl, pyridoimidazolyl, pyrimidoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl and naphthyridinyl. Examples of saturated or partially saturated heterocyclic rings include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, benzodioxyl and dihydropyrimidinyl. This definition further comprises sulphur-containing rings wherein the sulphur atom has been oxidised to an S(O) or S(O2) group.

The term “aromatic ring” refers to a 5-10 membered aromatic mono or bicyclic ring optionally containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur. Examples of such “aromatic rings” include: phenyl, pyrrolyl, pyrazolyl, furanyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl and thienyl. Preferred aromatic rings include phenyl, thienyl and pyridyl. The symbol

denotes where the respective group is linked to the remainder of the molecule.

For the avoidance of doubt where two groups or integers appear within the same definition, for example, —(CH₂)_(s)-L-(CH₂)_(s)— or R⁹R¹⁰NSO₂N(R¹⁰)—, then these can be the same of different.

For the avoidance of doubt, where several groups together form a ring, for example: ‘the group

forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms’, then the groups shown cyclises to form a ring, i.e

the component of which are defined by the definitions of the groups which form the ring, thus in the above example the ring would include a nitrogen atom. For example in Example 5 this group forms a piperazine ring.

The term C₁₋₃perfluoroalkyl refers to a C₁₋₃alkyl chain in which all hydrogens have been replaced with a fluorine atom. Examples of C₁₋₃perfluoroalkyl include trifluoromethyl, pentafluoroethyl and 1-trifluoromethyl-1,2,2,2-tetrafluoroethyl-. Preferably C₁₋₃perfluoroalkyl is trifluromethyl.

Examples of C₁₋₈alkyl include: methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl and 2-methyl-pentyl; example of C₁₋₈alkylene include: methylene, ethylene and 2-methyl-propylene; examples of C₁₋₆alkenyl include allyl (2-propenyl) and 2-butenyl, examples of C₁₋₆alkynyl 2-propynyl and 3-butynyl, examples of haloC₁₋₆alkyl include fluoroethyl, chloropropyl and bromobutyl, examples of hydroxyC₁₋₆alkyl include hydroxymethyl, hydroxyethyl and hydroxybutyl, examples of C₁₋₈alkoxy include methoxy, ethoxy and butyloxy; examples of C₁₋₄alkoxyC₁₋₄alkyl include methoxyethyl, propoxybutyl and propoxymethyl, examples of C₁₋₆alkanoyl incude formyl, ethanoyl, propanoyl or pentanoyl, examples of N—C₁₋₄alkylamino include N-methylamino and N-ethylamino; examples of N,N-di-C₁₋₄alkylamino include N,N-dimethylaminoethyl, N,N-di-methylaminopropyl and N,N-dipropylaminoethyl, examples of HO—C₂₋₄alkyl-NH include hydroxymethylamino hydroxyethylamino and hydroxypropyamino, examples of HO—C₂₋₄alkyl-N(C₁₋₄alkyl) include N-methyl-hydroxymethylamino, N-ethyl-hydroxyethylamino, and N-propyl-hydroxypropyamino, examples of C₁₋₆alkyl-S(O_(n))-methylthio, methylsulphinyl, ethylsulphinyl, ethylsulphonyl and propylsulphonyl, include examples of arylC₁₋₆alkyl include benzyl, phenethyl and phenylbutyl, examples of heterocyclylC₁₋₆alkyl include pyrrolidin-1-yl ethyl, imidazolylethyl, pyridylmethyl and pyrimidinylethyl.

It is to be understood that, insofar as certain of the compounds of the invention may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of antagonizing gonadotropin releasing hormone (GnRH) activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, activity of these compounds may be evaluated using the standard laboratory techniques referred to hereinafter.

The invention also relates to any and all tautomeric forms of the compounds of the different features of the invention that possess the property of antagonizing gonadotropin releasing hormone (GnRH) activity.

It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms which possess the property of antagonizing gonadotropin releasing hormone (GnRH) activity.

Preferred compounds of Formula (I), Formula (Ia) and Formula (Ib) are those wherein any one of the following apply.

Preferably R¹ is selected from hydrogen or optionally substituted C₁₋₆alkyl. More preferably R¹ represents hydrogen or unsubstituted C₁₋₆alkyl. Yet more preferably R¹ represents hydrogen, methyl, ethyl or tert-butyl. Most preferably R¹ represents hydrogen.

Preferably optional substituents on R¹ are independently selected from: optionally substituted C₁₋₄alkyl, optionally substituted C₂₋₆alkenyl, cyano, nitro, C₁₋₃perfluoroalkyl, C₁₋₃perfluoroalkoxy, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl, R⁹O(CH₂)_(v)—; R⁹C(O)O(CH₂)_(v)—, R⁹OC(O)(CH₂)_(v)—, R¹⁶S(O_(n))(CH₂)_(v)—, R⁹R¹⁰NC(O)(CH₂)_(v)—, or halo wherein v is an integer between 0 and 4, and where 2 optional substituents are present together they can optionally form a C₃₋₇carbocyclic ring or a heterocyclic ring.

Preferably R² is an optionally substituted monocyclic aromatic ring structure. Most preferably R² represents optionally substituted phenyl.

Preferably optional substituents on R² are independently selected from: optionally substituted C₁₋₆-alkyl, optionally substituted C₂₋₆alkenyl, cyano, nitro, C₁₋₃perfluoroalkyl, C₁₋₃perfluoroalkoxy, optionally substituted aryl, optionally substituted arylC₁₋₆-alkyl, R⁹O(CH₂)_(p)—, R⁹C(O)O(CH₂)_(w)—, R⁹OC(O)(CH₂)_(w)—, R¹⁶S(O_(n))(CH₂)_(w)—, R⁹R¹⁰NC(O)(CH₂)_(w)—, R⁹R¹⁰N— or halo; wherein w is an integer between 0 and 4 and R⁹ and R¹⁰ are as defined above. Further preferably the optional substituents on R² are independently selected from cyano, R^(e)R^(f)N—, optionally substituted C₁₋₆alkyl (preferably, C₁₋₄alkyl, eg, methyl or ethyl), optionally substituted C₁₋₆alkoxy (preferably, C₁₋₄alkoxy, eg, methoxy, ethoxy or tert-butoxy) or halo (eg, F, Br or Cl) wherein R^(e) and R^(f) are independently selected from hydrogen, C₁₋₆alkyl or aryl. Yet further preferably optional substituents on R² are independently selected from methyl, ethyl, methoxy, ethoxy, tert-butoxy, F or Cl. Most preferably optional substituents on R² are independently selected from methyl, F or Cl. Preferably R² bears 1, 2 or 3 substituents.

Most preferably R² represents

Preferably R³ is selected from a group of Formula (IIa) Formula (IIb), Formula (IIc) or Formula (IId). Further preferably R³ is selected from Formula (IIa) or Formula (IIb). Most preferably R³ is a group of Formula (IIb). Preferably the group of Formula (III):

is selected from a group of Formula III-a; III-b; III-c; III-d; III-e; III-f, III-g, III-h, III-i, or III-j, III-k or III-l;

wherein:

-   -   het represents an optionally substituted 3- to 8-membered         heterocyclic ring containing from 1 to 4 heteroatoms         independently selected from O, N and S;     -   R²³ and R^(23a) are independently selected from:         -   (i) hydrogen or optionally substituted C₁₋₈alkyl; or         -   (ii) R²³ and R^(23a) together with the carbon to which they             are attached form an optionally substituted 3 to 7-membered             cycloalkyl ring;     -   R²⁴ and R²⁵ are selected from:         -   (i) R²⁴ selected from hydrogen; optionally substituted             C₁₋₈alkyl; optionally substituted aryl; —R^(d)—Ar, where             R^(d) represents C₁₋₈alkylene and Ar represents optionally             substituted aryl; and optionally substituted 3- to             8-membered heterocyclic ring optionally containing from 1 to             3 further heteroatoms independently selected from O, N and             S; and R²⁵ is selected from hydrogen; optionally substituted             C₁₋₈alkyl and optionally substituted aryl;         -   (ii) wherein the group of Formula (III) represents a group             of Formula III-a, III-b or III-i, then the group NR²⁴(—R²⁵)             represents an optionally substituted 3- to 8-membered             heterocyclic ring optionally containing from 1 to 3 further             heteroatoms independently selected from O, N and S; or         -   (iii) wherein the group of Formula (III) represents             structure III-e,         -    represents an optionally substituted 3- to 8-membered             heterocyclic ring optionally containing from 1 to 4             heteroatoms independently selected from O, N and S;

More preferably the group of Formula (III) is selected from a group of Formula III-a, III-g, III-h, III-i, III-j, III-k or III-l:

wherein R²³, R^(23a), R²⁴ and R²⁵ are as defined above.

Further preferably the group of Formula (III) is selected from one of the following groups:

wherein R²³, R^(23a), R²⁴ and R²⁵ are as defined above.

Yet further preferably the group of Formula (III) is selected from one of the following groups:

wherein Me represents methyl.

Yet further preferably the group of Formula (III) is selected from one of the following groups:

Most preferably the group of Formula (III) is:

Preferably R⁶ and R^(6a) are independently selected from hydrogen, fluoro, optionally substituted C₁₋₆alkyl or R⁶ and R^(6a) taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms More preferably R⁶ and R^(6a) are independently selected from hydrogen, unsubstituted C₁₋₆alkyl or R⁶ and R^(6a) taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms. Yet more preferably R⁶ and R^(6a) are independently selected from hydrogen, methyl or R⁶ and R^(6a) taken together and the carbon atom to which they are attached form cyclopropyl. Most preferably R⁶ is hydrogen and R^(6a) is methyl.

Preferably R⁷ is selected from: hydrogen or C₁₋₄alkyl. More preferably R⁷ is hydrogen or methyl. Most preferably R⁷ is hydrogen.

When R⁸ is heterocyclyl then R⁸ is preferably selected from one of the following groups:

wherein Z is selected from: O, S or N(R⁹), R²⁰ is selected form any group within the definitions of R¹² and R¹³, and R⁹, R¹², R¹³ and R¹⁴ are as defined above.

In a further embodiment of the invention when R⁸ is heterocyclyl then R⁸ is preferably selected from one of the following groups:

wherein Z is selected from: O, S or N(R⁹) and R⁹, R¹² and R¹³ are as defined above.

When R⁸ is aryl or aryl-(C)-aryl optionally substituted by R¹², R¹³ and R¹⁴, R⁸ is preferably selected one of the following groups:

wherein D is selected from group E, group F or a direct bond;

Preferably R⁸ is selected from

-   -   (i) hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, haloC₁₋₆alkyl, hydroxy,         cyano, C₁₋₆alkylS(O_(n))—, —O—R^(b), C₁₋₄alkoxyC₁₋₄alkyl,         —C(O)—R^(b), C(O)O—R^(b), —NH—C(O)—R^(b), N,N-di-C₁₋₄alkylamino,         S(O_(n))NR^(b)R^(c)         -   where R^(b) and R^(c) are independently selected from             hydrogen and C₁₋₆alkyl, and n is 0, 1 or 2;     -   (ii) -(Q)-aryl, optionally substituted by up to 3 groups         selected from R¹², R¹³ and R¹⁴;     -   (iii) C₄₋₇heterocyclyl, optionally substituted by up to 3 groups         selected from R¹², R¹³ and R¹⁴,         -   more preferably selected from: azirinyl, azetidinyl,             pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,             imidazolidinyl, piperidinyl, piperazinyl,             hexahydropyrimidinyl, hexahydropyridazinyl,             hexahydrotriazinyl, tetraydrotriazinyl, dihydrotriazinyl,             tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, dioxanyl,             trioxanyl, tetrahydrotienyl, 1-oxotetrahydrothienyl,             1,1-dioxotetrahydrothienyl tetrahydrothiopyran,             1-oxotetrahydrothiopyran, 1,1-dioxotetrahydrothiopyran,             dithianyl, trithianyl, morpholinyl, oxathiolanyl,             oxathianyl, thiomorpholinyl, thiazinanyl,             1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,             thiazolidinyl, pyrrolyl, imidazolyl, triazolyl, pyridyl,             pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, thiazolyl,             thiadiazolyl, thiadiazinyl, oxazolyl, isoxazolyl,             oxadiazolyl, furazanyl, octahydropyrrolopyrrolyl,             octahydropyrrolopyrrolyl, benzotriazolyl,             dihydrobenzotriazolyl, indolyl, indolinyl, benzimidazolyl,             2,3-dihydrobenzimidazoly, benzotriazolyl 2,3-dihydro             benzotriazolyl quinolinyl, isoquinolinyl, cinnolinyl,             phthalazinyl, quinazolinyl, quinozalinyl, naphthyridinyl,             pteridinyl, benzodioxolyl, tetrahydrodioxolopyrrolyl,             1,5-dioxa-9-azaspiro[5.5]undecanyl or             8-oxa-3-azabicyclooctanyl; each of which is optionally             substituted by up to 3 groups selected from R¹², R¹³ and R¹⁴             or     -   (iv) C₃₋₇carbocyclyl; optionally substituted by up to 3 groups         selected from R¹², R¹³ and R¹⁴;

Further preferably R⁸ is selected from

-   -   (i) hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, haloC₁₋₆alkyl, hydroxy,         cyano, C₁₋₆alkylS(O_(n))—, —O—R^(b), C₁₋₄alkoxyC₁₋₄alkyl,         —C(O)—R^(b), C(O)O—R^(b), —NH—C(O)—R^(b), N,N-di-C₁₋₄alkylamino,         —S(O_(n))NR^(b)R^(c)         -   where R^(b) and R^(c) are independently selected from             hydrogen and C₁₋₆alkyl, and n is 0, 1 or 2;         -   preferably selected from: hydrogen, methyl, isopropyl,             t-butyl, 1-methylethyl, allyl, fluoroethyl, hydroxy, cyano,             ethylsulphonyl, methoxy, 1-methyl-2-methoxyethyl, acetyl,             t-butoxycarbonyl, acetylamino, dimethylamino, diethylamino,             (1-methylethyl)amino, isopropylamino or aminosulphonyl;     -   (ii) -(Q)-aryl, wherein aryl is optionally substituted by up to         3 groups selected from R¹², R¹³ and R¹⁴;     -   (iii) azetidinyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl,         pyrrolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl,         morpholinyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl,         thiomorpholinyl, 1-oxo-thiomorpholinyl,         1,1-dioxo-thiomorpholinyl, imidazolyl, triazolyl, thienyl,         thiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl,         tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrolyl,         1,5-dioxa-9-azaspiro[5.5]undecanyl,         8-oxa-3-azabicyclo[3.2.1]octanyl, benzodioxolyl,         2,3-dihydrobenzotriazolyl, 1,2-dihydroquinolinyl or         octahydropyrrolo[3,4-c]pyrrolyl; each of which is optionally         substituted by up to 3 groups selected from R¹², R¹³ and R¹⁴; or     -   (iv) C₃₋₇carbocyclyl, optionally substituted by up to 3 groups         selected from R¹², R¹³ and R¹⁴;

Yet further preferably R⁸ is selected from

-   -   (i) phenyl optionally substituted by up to 3 groups selected         from R¹², R¹³ and R¹⁴ or naphthyl;     -   (ii) furanyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl,         morpholinyl, 1,1-dioxo-thiomorpholinyl, thienyl, triazolyl,         pyridyl, pyrimidinyl, pyrazinyl,         tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrolyl, benzodioxolyl,         1,2-dihydroquinolinyl or 2,3-dihydrobenzotriazolyl; each of         which is optionally substituted by up to 3 groups selected from         R¹², R¹³ and R¹⁴; or     -   (iii) C₃₋₇carbocyclyl (preferably cyclohexyl or cylopentyl, more         preferably cyclohexyl) optionally substituted by up to 3 groups         selected from R¹², R¹³ and R¹⁴;

Further preferably R⁸ is selected from: phenyl, thienyl, pyridyl and benzodioxlyl optionally substituted by up to 3 groups selected from R¹², R¹³ and R¹⁴.

Most preferably R⁸ is 1,3 benzodioxolyl.

In another embodiment of the invention R⁸ is selected from piperidinyl or piperazinyl, azetidinyl, imidazolyl and thiazolyl, each of which is optionally substituted by up to 3 groups selected from R¹², R¹³ and R¹⁴.

In a further embodiment of the invention preferably R⁸ is selected from hydrogen, cyano, C₁₋₄alkyl (more preferably methyl), C₂₋₆alkynyl (more prefeably 2-propynyl), hydroxyC₁₋₆alkyl (more preferably hydroxyethyl), C₁₋₄alkoxyC₁₋₄alkyl (more preferably methoxyethyl), haloC₁₋₆alkyl (more preferably fluoroethyl), C₁₋₄alkanoyl (more preferably formyl), C₁₋₄alkoxycarbonyl (more preferably butyloxycarbonyl), N,N-di-C₁₋₄alkylamino (more preferably N,N-dimethylaminoethyl and N,N-dimethylaminopropyl), C₁₋₆alkyl-S(O_(n))— (more preferably ethylsulphonyl), cyclopentyl, phenyl, benzyl, cyanophenyl, pyrrolidinyl, pyrrolidinylethyl, imidazolyl, imidazolyC₁₋₆alkyl (more preferably imidazolylethyl), thiazolyl, pyridyl, pyridylC₁₋₆alkyl (more preferably pyridylmethyl) or pyrimidyl wherein a phenyl or heterocyclyl ring is optionally substituted by C₁₋₄alkyl or halo.

When R⁹ and/or R¹⁰ is a component of group G, R⁹ and R¹⁰ are preferably independently selected from hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl or R⁹ and R¹⁰ forms C₃₋₇cycloalkyl or heterocyclyl. Further preferably hydrogen or C₁₋₄alkyl. Most preferably hydrogen or methyl. Most preferably both R⁹ and R¹⁰ are methyl.

When R⁹ and/or R¹⁰ is a component of group R¹⁸, R⁹ and R¹⁰ are preferably independently selected from hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl or R⁹ and R¹⁰ forms C₃₋₇cycloalkyl or heterocyclyl. Further preferably when R⁹ is a component of group R¹⁸, R⁹ is preferably heterocyclyl. Most preferably pyrrolidinyl, 7-azabicyclo[2.2.1]hept-7-yl or. 3-azabicyclo[3.2.2]nonyl.

Preferably R¹⁷ is hydrogen, hydroxy, cyano or is absent. Most preferably R¹⁷ is absent.

Preferably R¹⁸ is selected from hydrogen, R⁹N(R¹⁰)C(O)—, R⁹C(O)—, R⁹OC(O) or R^(18a)—C(R⁹R¹⁰)— wherein R^(18a) is R⁹N(R¹⁰)C(O)—. Further preferably R⁹C(O)—. Most preferably R⁹C(O)— wherein R⁹ is heterocyclyl.

Preferably A is selected from a direct bond, optionally substituted C₁₋₅alkylene, carbonyl or —C(O)—C(R^(d)R^(d))—, wherein R^(d) is independently selected from a direct bond hydrogen and C₁₋₂alkyl. Further preferably A is selected from C₁₋₅alkylene optionally substituted with C₁₋₄alkyl, carbonyl or carbonylmethyl. Yet further preferably A is a direct bond methylene. Most preferably methylene.

Preferably B is selected from optionally substituted C₁₋₆alkylene, optionally substituted C₃₋₆alkenylene, —(C₁₋₅alkyl)_(aa)-O—(C₁₋₅alkyl)_(bb), —(C₁₋₅alkyl)_(aa)-C(O)—(C₁₋₅alkyl)_(bb)-, —(CH₂)_(s1)—C(O)N(R⁹)—(CH₂)_(s2)—, or the group

forms an optionally substituted C₄₋₇ heterocyclic ring, wherein aa and bb are independently 0 to 1 and, wherein the combined length of (C₁₋₅alkyl)_(aa) and (C₁₋₅alkyl)_(bb) is less than or equal to C₅alkyl.

More preferably B is C₁₋₆alkylene, C₃₋₆alkenylene, —(C₁₋₅alkyl)_(aa)-O—(C₁₋₅alkyl)_(bb)-, —(C₁₋₅alkyl)_(aa)-C(O)—(C₁₋₅alkyl)_(bb)-, —(CH₂)_(s1)—C(O)N(R⁹)—, or the group

forms an optionally substituted saturated C₄₋₇ heterocyclic ring, wherein aa and bb are independently 0 or 1 and wherein the combined length of (C₁₋₅alkyl)_(aa), (C₁₋₅alkyl)_(bb) is less than or equal to C₅alkyl and wherein C₁₋₆alkylene is optionally substituted by hydroxy.

Further preferably B is unsubstituted C₁₋₆alkylene, C₃₋₆alkenylene —(C₁₋₅alkyl)_(aa)-O—(C₁₋₅alkyl)_(bb)-, —(C₁₋₅alkyl)_(aa)-C(O)— or the group

forms an optionally substituted saturated C₄₋₇ heterocyclic ring selected from: azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, hexahydrotriazinyl, tetraydrotriazinyl, dihydrotriazinyl, morpholinyl, thiomorpholinyl, thiazinanyl, thiazolidinyl, 1,5-dioxa-9-azaspiro[5.5]undecanyl or octahydropyrrolopyrrolyl, wherein the optional substituents are selected from. cyano, hydroxy, oxo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, R⁹OC(O)(CH₂)_(w)—, R⁹R¹⁰NC(O)(CH₂)_(w)— or halo, wherein w is an integer between 0 and 4 and R⁹ and R¹⁰ are as defined above. Further preferably the optional substituents are selected from: cyano, hydroxy, oxo, C₁₋₄alkyl, C₁₋₄alkoxy and C₁₋₄alkanoyl, aa and bb are independently 0 or 1, wherein the combined length of (C₁₋₅alkyl)_(aa) and (C₁₋₅alkyl)_(bb) is less than or equal to C₅alkyl and wherein C₁₋₆alkylene is optionally substituted by hydroxy.

Yet further preferably B is selected from: methylene, ethylene, propylene, propyl-2-ene, butylene, pentylene, 2-propenyl, propoxy, ethoxyethyl, methylcarbonyl or methylcarbonylamino. or the group

forms an C₄₋₇ heterocyclic ring selected from: pyrrolidinyl, piperidinyl, or piperazinyl, wherein the optional substituents are selected from oxo.

Most preferably B is selected from ethylene or butylene.

In another embodiment of the invention preferably B is selected from optionally substituted C₁₋₆alkylene or the group

forms a C₅₋₇ heterocyclic ring. Preferably unsubstituted C₋₆alkylene or a C₅₋₇ heterocyclic saturated ring. Most preferably methylene, ethylene, propylene, butylene or piperazinyl.

Peferably G is a direct bond, —O— or —C(R⁹R¹⁰)—. More preferably —C(R⁹R¹⁰)—. Most preferably —C(CH₃)₂—.

Preferably M is —CH₂—O—.

When R³ is selected from a group of Formula (IIc) or Formula (IId) then the group

preferably forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms.

More preferably the group

forms an optionally substituted saturated C₄₋₇ heteocyclic ring.

Further preferably the group

forms an optionally substituted saturated C₄₋₇ heteocyclic ring selected from: azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, hexahydrotriazinyl, tetraydrotriazinyl, dihydrotriazinyl, morpholinyl, thiomorpholinyl, thiazinanyl, thiazolidinyl or octahydropyrrolopyrrolyl, wherein the optional substituents are selected from oxo.

Further preferably the group

forms an optionally substituted saturated C₄₋₇ heteocyclic ring selected from: pyrrolidinyl, piperidinyl or piperazinyl, wherein the optional substituents are selected from oxo.

Most preferably the group

forms an optionally substituted saturated C₄₋₇ heteocyclic ring selected from: piperazinyl.

Preferably K is selected from: —(CH₂)_(s)—, —(CH₂)_(s)—O—(CH₂)_(s)—, —(CH₂)_(s)—C(O)—(CH₂)_(s)—, —(CH₂)_(s)—N(R¹⁸)—(CH₂)_(s)—, —(CH₂)_(s)—C(O)N(R¹⁸)—(CH₂)—, —(CH₂)_(s)—N(R¹⁸)C(O)—(CH₂)_(s)—, —(CH₂)_(s)—S(O)₂N(R¹⁸)—(CH₂)_(s)—, or —(CH₂)_(s)—NHS(O)₂—(CH₂)_(s)—,

wherein s is independently selected from 0, 1, 2, 3 or 4, R¹⁸ is selected from hydrogen or C₁₋₄alkyl (preferably hydrogen) and the —(CH₂)_(s)— group is optionally substituted by hydroxy or C₁₋₄alkyl.

More preferably K is selected from: —(CH₂)_(s)—, —(CH₂), —O—(CH₂)_(s)—, —(CH₂)_(s)—C(O)—, —C(O)(CH₂)_(s)—, —(CH₂)_(s)—N(R⁸)—, —(CH₂)_(s)—C(O)N(R¹⁸)—, —(CH₂)_(s)—N(R¹⁸)C(O)—(CH₂)_(s)—, —(CH₂)_(s)—S(O)₂N(R¹⁸)— or —(CH₂)_(s)—NHS(O)₂—,

wherein s is independently selected from 0, 1, 2, 3 or 4, R¹⁸ is selected from hydrogen or C₁₋₄alkyl (preferably hydrogen or methyl) and the —(CH₂)_(s)— group is optionally substituted by hydroxy or C₁₋₄alkyl.

More preferably K is selected from: methylene, ethylene, propylene, butylene, oxy, 2-hydroxypropylene, carbonyl, methylcarbonyl, ethylcarbonyl, (methyl)methylcarbonyl, (ethyl)methylcarbonyl, carbonylmethylene, carbonylethylene, ethoxyethylene, amino, 2-hydroxypropylamino, carbonylamino, methylcarbonylamino, N-methyl-methylcarbonylamino, aminocarbonyl, methylaminocarbonyl, methylaminocarbonylmethyl, propylsulphonylamino or methylaminosulphonyl.

Further preferably K is selected from: methylene, ethylene, propylene, butylene carbonyl, methylcarbonyl or N-methylmethylcarbonylamino.

Most preferably K is selected from: methylcarbonyl and N-methylmehtylcarbonylamino.

Preferably optional substituents on heterocyclyl groups in R⁸, R⁹, R¹⁰, R¹⁸ and R¹⁹ or on heterocyclyl groups formed when R¹⁷ and R¹⁸ together form a heterocyclic ring are selected from: optionally substituted C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, optionally substituted C₂₋₆alkenyl, cyano, nitro, C₁₋₃perfluoroalkyl, C₁₋₃perfluoroalkoxy, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl, R⁹O(CH₂)_(p)—, R⁹C(O)O(CH₂)_(w)—, R⁹OC(O)(CH₂)_(w)—, R¹⁶S(O_(n))(CH₂)_(w)—, R⁹R¹⁰NC(O)(CH₂)_(w)— or halo; wherein w is an integer between 0 and 4 and p, R⁹, R¹⁰ and R¹⁶ are as defined above.

More preferably optional substituents on R⁸ are selected from: cyano, hydroxy, oxo, nitro, halo, trifluromethyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, R⁹OC(O)(CH₂)_(w)—, R⁹R¹⁰N(CH₂)_(w)—, R⁹R¹⁰NC(O)(CH₂)_(w)—, R⁹R¹⁰NC(O)(CH₂)_(w)—, R⁹R¹⁰NC(O)N(R⁹)(CH₂)_(w)—, R⁹OC(O)N(R⁹)(CH₂)_(w)—, or halo, wherein w is an integer between 0 and 4 and R⁹ and R¹⁰ are selected from: hydrogen, C₁₋₄alkyl, C₁₋₄alkylsulphonyl and C₃₋₇carbocyclyl.

Further preferably optional substituents on R⁸ are selected from: cyano, hydroxy, oxo, amino, N,N-diC₁₋₄alkyamino, N,N-diC₁₋₄alkyaminoC₁₋₄alkyl, N′—C₁₋₄alkylureido, N—C₁₋₄alkylsulphonylamino, N,N-di-C₁₋₄alkylsulphonylamino, nitro, halo, trifluoromethyl, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C1-4alkoxycarbonylamino and C₃₋₇carbocyclylcarbonylamino.

More preferably optional substituents on R⁸ are selected from: cyano, oxo, methyl, t-butyl, methoxy, acetyl, amino, N,N-diethylamino, N′-isopropylureido, N′-cyclohexylureido, N-methylsulphonylamino, N,N-dimethylsulphonylamino, nitro, chloro, fluoro, trifluoromethyl, isopropoxycarbonylamino and cyclopentylcarbonylamino.

Most preferably optional substituents on R⁸ are selected from: methoxy, fluoro, methylsulphonylamino and isopropoxycarbonylamino.

In a further embodiment of the invention optional substituents on R⁸ are selected from: C₁₋₄alkoxy, fluoro, C₁₋₄alkylsulphonylamino, C₁₋₄alkanoylamino, C₁₋₄alkylureido and C₁₋₄alkoxycarbonylamino.

In a further embodiment of the invention when R⁸ is phenyl then R⁸ is preferably substituted and when R⁸ is a heterocyclic ring R⁸ is preferably unsubstituted.

Preferably the optional substituents on alkyl, alkenyl, alkyl, cycloalkyl and aryl groups are independently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₇cycloalkyl, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl, hydroxy, oxo, cyano, C₁₋₆alkoxy, halo (preferably fluoro), R¹⁶S(O_(n))(CH₂)_(w)—, R⁹OC(O)—, optionally substituted arylC₁₋₃alkoxy wherein R⁹ is as defined above.

Preferably the optional substituents on optionally substituted aryl and arylC₁₋₆alkyl groups are selected from: optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆alkenyl, cyano, nitro, halo (preferably fluoro), C₁₋₃perfluoroalkyl, C₁₋₃perfluoroalkoxy, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl, R⁹O(CH₂)_(p)—, R⁹C(O)O(CH₂)_(w)—, R⁹OC(O)(CH₂)_(w)—, R¹⁶S(O_(n))(CH₂)_(w)—, R⁹R¹⁰NC(O)(CH₂)_(w)— or halo; wherein w is an integer between 0 and 4 and n, R⁹ and R¹⁰ are as defined above.

In preferences for heterocyclyl in R⁸ the nitrogen atoms contained in R⁸ heteroaromatic rings exist either as drawn or, where chemically allowed, in their oxidised (N→O, N—OH) state.

Where optional substitution is mentioned at various places the optional substituents also comprise the following definition which refers to one, two, three or more optional substituents. Unless otherwise indicated above (i.e., where a list of optional substituents is specifically listed within a definition), each substituent can be independently selected from C₁₋₈alkyl (eg, C₂₋₆alkyl, and most preferably methyl, ethyl or tert-butyl); C₃₋₈cycloalkoxy, preferably cyclopropoxy, cyclobutoxy or cyclopentoxy; C₁₋₆alkoxy, preferably methoxy or C₂₋₄alkoxy; halo, preferably Cl or F; Hal₃C—, Hal₂CH₂—, HalCH₂—, Hal₃CO—, Hal₂CHO or Hal CH₂O, wherein Hal represents halo (preferably F); R^(g)CH₂O—, R^(h)C(O)NR)—, R^(h)SO₂N(R)— or R^(g)—R^(h)N—, wherein R^(g) and R^(h) independently represent hydrogen or C₁₋₈alkyl (preferably methyl or C₂₋₆alkyl or C₂₋₄alkyl), or R^(g)—R^(h)N— represents an optionally substituted C₃₋₈, preferably C₃₋₆, heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; hydrogen; or R^(k)C(O)O— or R^(k)C(O)—, R^(k) representing hydrogen, optionally substituted phenyl or C₁₋₆alkyl (preferably methyl, ethyl, iso-propyl or tert-butyl). For optional substitution of the heterocyclic ring represented by R^(g)—R^(h)N—, at least one (eg, one, two or three) substituents may be provided independently selected from C₁₋₆alkyl (eg, C₂₋₄alkyl, more preferably methyl); phenyl; CF₃O—; F₂CHO—; C₁₋₈alkoxy, preferably methoxy, ethoxy or C₃₋₆alkoxy; C₁₋₈alkoxyC(O), preferably methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or C₃₋₆alkoxyC(O); phenoxycarbonyl; phenoxy; C₁₋₈alkanoyl, preferably acetyl, ethanoyl or C₃₋₆alkyanoyl; carboxy; C₁₋₈alkylS(O_(nn)) wherein nn is an integer between 0 and 2, preferably methylthio, ethylthio, C₃₋₆alkylthio, methylsulphinyl, ethylsulphinyl, C₃₋₆alkylsulphinyl, methylsulphonyl, ethylsulphonyl or C₃₋₆alkylsulphonyl; hydroxy; halo (eg, F, Cl or Br); R^(m)R^(n)N— where R^(m) and R^(n) are independently hydrogen or C₁₋₆alkyl (preferably C₂₋₄alkyl, more preferably methyl, most preferably R^(m)═R^(n)=methyl); and nitro.

According to a further aspect of the invention there is provided a compound of Formula (Ib)

wherein:

-   -   R¹ represents hydrogen or unsubstituted C₁₋₆alkyl;     -   R² represents optionally substituted phenyl;     -   R³ is selected from a group of Formula (IIa) to Formula (IId):     -   R⁵ is selected from a one of a group of Formula III-a to III-l:     -   wherein:         -   het represents an optionally substituted 3- to 8-membered             heterocyclic ring containing from 1 to 4 heteroatoms             independently selected from O, N and S;         -   R²³ and R^(23a) are independently selected from:             -   (i) hydrogen or optionally substituted C₁₋₈alkyl; or             -   (ii) R²³ and R^(23a) together with the carbon to which                 they are attached form an optionally substituted 3 to                 7-membered cycloalkyl ring;         -   R²⁴ and R²⁵ are selected from:             -   (i) R²⁴ selected from hydrogen; optionally substituted                 C₁₋₈alkyl; optionally substituted aryl; —R^(d)—Ar, where                 R^(d) represents C₁₋₈alkylene and Ar represents                 optionally substituted aryl; and optionally substituted                 3- to 8-membered heterocyclic ring optionally containing                 from 1 to 3 further heteroatoms independently selected                 from O, N and S; and R²⁵ is selected from hydrogen;                 optionally substituted C₁₋₈alkyl and optionally                 substituted aryl;             -   (ii) wherein the group of Formula (III) represents a                 group of Formula III-a, III-b or III-i, then the group                 NR²⁴(—R²⁵) represents an optionally substituted 3- to                 8-membered heterocyclic ring optionally containing from                 1 to 3 further heteroatoms independently selected from                 O, N and S; or             -   (iii) wherein the group of Formula (III) represents                 structure III-e,                 represents an optionally substituted 3- to 8-membered                 heterocyclic ring optionally containing from 1 to 4                 heteroatoms independently selected from O, N and S;     -   R⁶ and R^(6a) are independently selected from hydrogen, fluoro         or optionally substituted C₁₋₆alkyl.     -   R⁷ is selected from: hydrogen or C₁₋₄alkyl;     -   R⁸ is selected from         -   (i) hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, haloC₁₋₆alkyl,             hydroxy, cyano, C₁₋₆alkylS(O_(n))—, —O—R^(b),             C₁₋₄alkoxyC₁₋₄alkyl, —C(O)—R^(b), C(O)O—R^(b),             —NH—C(O)—R^(b), N,N-di-C₁₋₄alkylamino or             —S(O_(n))NR^(b)R^(c)             -   where R^(b) and R^(c) are independently selected from                 hydrogen and C₁₋₆alkyl, and n is 0, 1 or 2;         -   (ii) -aryl, optionally substituted by up to 4 substituents             selected from R¹², R¹³ and R¹⁴;         -   (iii) C₄₋₇ heterocyclyl, optionally substituted by up to 4             substituents selected from R¹², R¹³ and R¹⁴; or         -   (iv) C₃₋₇carbocyclyl, optionally substituted by up to 4             substituents selected from R¹², R¹³ and R¹⁴;     -   R⁹ and R¹⁰ are independently selected from: hydrogen, hydroxy,         optionally substituted C₁₋₆alkyl, optionally substituted aryl,         optionally substituted arylC₁₋₆alkyl, an optionally substituted         carbocyclic ring of 3-7 atoms, optionally substituted         heterocyclyl, optionally substituted heterocyclylC₁₋₆alkyl or R⁹         and R¹⁰ taken together can form an optionally substituted ring         of 3-9 atoms or R⁹ and R¹⁰ taken together with the carbon atom         to which they are attached form a carbonyl group;     -   R¹² is selected from: hydrogen, hydroxy, R¹⁷R¹⁸N(CH₂)_(cc)—,         R¹⁷R¹⁸NC(O)(CH₂)_(cc)—, optionally substituted         C₁₋₆alkyl-C(O)N(R⁹)(CH₂)_(cc)—, optionally substituted         C₁₋₆alkyl-SO₂N(R⁹)—, optionally substituted aryl-SO₂N(R⁹)—,         C₁₋₃perfluoroalkyl-SO₂N(R⁹)—; optionally substituted         C₁₋₆alkyl-N(R⁹)SO₂—, optionally substituted aryl-N(R⁹SO₂—,         C₁₋₃perfluoroalkyl-N(R⁹)SO₂— optionally substituted         C₁₋₆-alkanoyl-N(R⁹)SO₂—; optionally substituted         aryl-C(O)N(R⁹)SO₂—, optionally substituted C₁₋₆alkyl-S(O_(n))—,         optionally substituted aryl-S(O_(n))—, C₁₋₃perfluoroalkyl-,         C₁₋₃perfluoroalkoxy, optionally substituted C₁₋₆alkoxy, carboxy,         halo, nitro or cyano;     -   R¹³ and R¹⁴ are independently selected from: hydrogen, hydroxy,         oxo, optionally substituted C₁₋₆alkyl, optionally substituted         C₁₋₆alkanoyl, optionally substituted C₂₋₆alkenyl, cyano, nitro,         C₁₋₃perfluoroalkyl-, C₁₋₃perfluoroalkoxy, optionally substituted         aryl, optionally substituted arylC₁₋₆alkyl, R⁹O(CH₂)_(s)—,         R⁹(O)O(CH₂)_(s)—, R⁹OC(O)(CH₂)_(s)—, R¹⁶S(O_(n))(CH₂)_(s)—,         R⁹R¹⁰NC(O)(CH₂)_(s)— or halo; A is selected from optionally         substituted C₁₋₅alkylene, carbonyl or —C(O)—C(R^(d)R^(d))—,         wherein R^(d) is independently selected from hydrogen and         C₁₋₂alkyl;     -   R¹⁷ is independently selected from: hydrogen, hydroxy, cyano or         optionally substituted C₁₋₆alkyl;     -   R¹⁸ is a group of formula R^(18a)—C(R⁹R¹⁰)₀₋₁— wherein R^(18a)         is selected from: R¹⁹OC(O)—, R⁹R¹⁰NC(O)—, R⁹R¹⁰N—, R⁹C(O)—,         R⁹C(O)N(R¹⁰)—, R⁹R¹⁰NC(O)—, R⁹R¹⁰NC(O)N(R¹⁰)—, R⁹SO₂N(R¹⁰)—,         R⁹R¹⁰NSO₂N(R¹⁰)—, R⁹C(O)O—, R⁹OC(O)—, R⁹R¹⁰NC(O)O—, R⁹O—,         R⁹S(O_(n))—, R⁹R¹⁰NS(O_(n))—, hydrogen, optionally substituted         C₁₋₆alkyl, optionally substituted heterocyclyl;         -   or R¹⁷ and R¹⁸ when taken together form an optionally             substituted carbocyclic ring of 3-7 atoms or optionally             substituted heterocyclyl;     -   R¹⁹ is selected from: hydrogen, optionally substituted C₁₋₆alky,         optionally substituted aryl, optionally substituted         arylC₁₋₆alkyl, optionally substituted C₃₋₇cycloalkyl, optionally         substituted heterocyclyl or optionally substituted         heterocyclylC₁₋₆alkyl;     -   B is selected from optionally substituted C₁₋₆alkylene or the         group     -    forms an optionally substituted C₄₋₇ heterocyclic ring, wherein         the optional substituents are selected from R¹², R¹³ and R¹⁴;     -   the group     -    preferably forms an optionally substituted heterocyclic ring         containing 4-7 carbons atoms, wherein the optional substituents         are selected from R¹², R¹³ and R¹⁴;     -   K is selected from: a direct bond, —(CH₂)_(s1)—,         —(CH₂)_(s2)—O—(CH₂)_(s)—, —(CH₂)_(s1)—C(O)—(CH₂)_(s2)—,         —(CH₂)_(s1)—S(O_(n))—(CH₂)_(s2)—,         —(CH₂)_(s1)—N(R¹⁸)—(CH₂)_(s2)—,         —(CH₂)_(s1)—C(O)N(R⁹)—(CH₂)_(s2)—,         —(CH₂)_(s1)—N(R⁹C(O)(CH₂)_(s2)—,         —(CH₂)_(s1)—N(R⁹)C(O)N(R⁹)—(CH₂)_(s2)—,         —(CH₂)_(s1)—OC(O)—(CH₂)_(s2)—, —(CH₂)_(s1)—C(O)O—(CH₂)_(s2)—,         —(CH₂)_(s1)—N(R⁹)C(O)O—(CH₂)_(s2)—,         —(CH₂)_(s1)—OC(O)N(R⁹)(CH₂)_(s2),         —(CH₂)_(s1)—OS(O_(n))—(CH₂)_(s2)—, or         —(CH₂)_(s1)—S(O_(n))—O—(CH₂)_(s2)—,         —(CH₂)_(s1)—S(O)₂N(R⁹)—(CH₂)_(s2)—,         —(CH₂)_(s1)—N(R⁹)S(O)₂—(CH₂)_(s2)—; wherein the —(CH₂)_(s1)— and         —(CH₂)_(s2)— groups are independently optionally substituted by         hydroxy, fluoro, cyano, carbamoyl, C₁₋₄alkyl and C₁₋₄alkoxy,     -   n is an integer from 0 to 2;     -   s1 and s2 are independently selected from an integer from 0 to         4, and s1+s2 is less than or equal to 4;     -   or a salt, pro-drug or solvate thereof.

According to a further aspect of the invention there is provided a compound of Formula (Ic)

-   -   wherein     -   R³ is selected from a group of Formula (IIa) or Formula (IIb):         and R¹, R², R⁵, R⁶, R^(6a), R⁷, R⁸, A, B and M are as defined         above;         or salt, solvate or pro-drug thereof.

A further preferred group of compounds of the invention comprises a compound of Formula (Ic), wherein:

-   -   A is optionally substituted C₁₋₅alkylene;     -   B is selected from optionally substituted C₁₋₆alkylene or the         group     -    forms a ring containing C₅₋₇ heterocyclic ring;     -   M is —CH₂—O—;     -   R¹ is hydrogen or C₁₋₄alkyl;     -   R⁶ and R^(6a), are independently selected from hydrogen and         optionally substituted C₁₋₄alkyl;     -   R⁷ is selected from: hydrogen or C₁₋₄alkyl;     -   R⁸ is selected from hydrogen, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl,         C₂₋₆alkynyl, C₁₋₆alkanoyl, C₁₋₄alkoxyC₁₋₄alkyl,         C₁₋₆alkoxycarbonyl, N,N-di-C₁₋₄alkylamino, aryl, arylC₁₋₆alkyl,         C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl, heterocyclyl,         heterocyclylC₁₋₆alkyl, or heterocyclylcarbonylC₁₋₄alkyl wherein         aryl and heterocyclyl rings are optionally substituted by cyano         and C₁₋₄alkyl; and     -   R² and R⁵; are as defined above         or salt, solvate or pro-drug thereof.

A further preferred group of compounds of the invention comprises a compound of Formula (Ic), wherein:

-   -   A is optionally substituted C₁₋₅alkylene;     -   B is selected from optionally substituted C₁₋₆alkylene or the         group     -    forms a ring containing C₅₋₇ heterocyclic ring;     -   R¹ is hydrogen or C₁₋₄alkyl, preferably hydrogen;     -   R² is an optionally substituted monocyclic aromatic ring         structure, preferably optionally substituted phenyl, most         preferably 3,5-dimethylphen-1-yl;     -   R⁵ is a group of Formula (III) wherein the group of         Formula (III) is selected from a group of Formula III-a; III-b;         III-c; III-d; III-e; III-f, III-g, III-h, III-I, III-j, III-k         and III-l;     -    wherein R²³, R^(23a), R²⁴ and R²⁵ are as defined above,         preferably the group of Formula (III) is selected from (III-a),         (III-g) and (III-h);     -   R⁶ and R^(6a), are independently selected from hydrogen and         optionally substituted C₁₋₄alkyl;     -   R⁷ is selected from: hydrogen or C₁₋₄alkyl;     -   R⁸ is selected from hydrogen, cyano, C₁₋₆alkyl, haloC₁₋₆alkyl,         C₂₋₆alkynyl, C₁₋₆alkanoyl, C₁₋₄alkoxyC₁₋₄alkyl,         C₁₋₆alkoxycarbonyl, N,N-di-C₁₋₄alkylamino, aryl, arylC₁₋₆alkyl,         C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl, heterocyclyl,         heterocyclylC₁₋₆alkyl, or heterocyclylcarbonylC₁₋₄alkyl wherein         aryl and heterocyclyl rings are optionally substituted by cyano         and C₁₋₄alkyl; and     -   R², and R⁵; are as defined above         or salt, solvate or pro-drug thereof.

A further preferred group of compounds of the invention comprises a compound of Formula (Id):

-   -   Wherein R¹, R², R⁵; R⁷, R⁸, A, B and M are as defined above         or salt, solvate or pro-drug thereof.

A yet further preferred group of compounds of the invention comprises a compound of Formula (Ib), (Ic) or (Id) wherein:

-   -   R⁵ is a group of Formula (III) wherein the group of         Formula (III) is a group of formula IIIa:     -   wherein R²³, R^(23a), R²⁴ and R²⁵ are as defined above;         or a salt, pro-drug or solvate thereof.

According to a further aspect of the invention there is provided a compound of Formula (I) or Formula (Ia), or salt, solvate or pro-drug thereof, wherein R³ is selected from a group of Formula (IIc) or Formula (IId) and R¹, R² and R⁵ are as defined above.

According to a further aspect of the invention there is provided a compound of Formula (I) or Formula (Ia), or salt, solvate or pro-drug thereof, wherein R³ is selected from a group of Formula (IIe) or Formula (IIf) and R¹, R² and R⁵ are as defined above.

According to a further aspect of the invention there is provided a compound of Formula (I) or Formula (Ia), or salt, solvate or pro-drug thereof, wherein R³ is selected from a group of Formula (IIa), Formula (IIc) or Formula (IIe) and R¹, R² and R⁵ are as defined above.

According to a further aspect of the invention there is provided a compound of Formula (I) or Formula (Ia), or salt, solvate or prodrug thereof, wherein R³ is selected from a group of Formula (IIb), Formula (IId) or Formula (IIf) and R¹, R² and R⁵ are as defined above.

Particularly preferred compounds according to the present invention are wherein the compound is selected from:

-   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-pyrid-4-ylethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-pyrid-4-ylbutyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[4-(4-methoxyphenyl)butyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-phenylethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(43-trifluoromethylphenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-fluorophenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(3-fluorophenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(3-methoxyphenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-methoxyphenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(3,4-difluorophenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-isopropylureidophenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-{cyclopentylcarbonylamino}phenyl)ethyl]-(2S)-propylamine; -   [2-(4-methylsulphonylaminophenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-{isopropoxycarbonylamino}phenyl)ethyl]-(2S)propylamine; -   2-[3-(2,2-diethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-{cyclohexylureido}phenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl]-(2S)propylamine; -   3-[2,2-dimethyl-3-oxo-3-(azabicyclo[2.2.2]oct-2-yl)propoxy]-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(3-methoxyphenyl)ethyl]-(2S)-propylamine;     and -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.2]oct-2-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine;     or a salt, pro-drug or solvate thereof.

More particularly preferred compounds according to the present invention are wherein the compound is selected from:

-   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-pyrid-4-ylethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-pyrid-4-ylbutyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[4-(4-methoxyphenyl)butyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(43-trifluoromethylphenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-fluorophenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(3-methoxyphenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-methoxyphenyl)ethyl]-(2S)-propylamine; -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-methylsulphonylaminophenyl)ethyl]-(2S)-propylamine;     and -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.2]oct-2-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)propylamine;     or a salt, pro-drug or solvate thereof.

Most preferred compounds according to the present invention are wherein the compound is selected from:

-   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine;     and -   2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.2]oct-2-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine;     or a salt, pro-drug or solvate thereof.

In another embodiment of the invention preferred compounds according to the present invention are wherein the compound is selected from:

-   2-[3-(2,2-dimethyl-3-oxo-3-pyrrolidin-1-ylpropoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-(2-pyridin-4-ylethyl)ethanamine; -   2-[3-(2,2-dimethyl-3-oxo-3-pyrrolidin-1-ylpropoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-(2-pyridin-4-ylbutyl)ethanamine; -   2-[3-(2,2-dimethyl-3-oxo-3-(7-azabicyclo[2.2.1]hept-7-yl)propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-(2-pyridin-4-ylethyl)ethanamine;     and -   2-[3-(2,2-dimethyl-3-oxo-3-(7-azabicyclo[2.2.1]hept-7-yl)propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-(2-pyridin-4-ylbutyl)ethanamine;     or a salt, pro-drug or solvate thereof.

The compounds of Formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the Formula (I). Examples of pro-drugs include in-vivo hydrolysable esters of a compound of the Formula (I). Various forms of pro-drugs are known in the art. For examples of such pro-drug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and     Methods in Enzymology, Vol. 42, p. 309-396, edited by K Widder, et     al. (Academic Press, 1985); -   b) A Textbook of Drug Design and Development, edited by     Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and     Application of Prodrugs”, by He Bundgaard p. 113-191 (1991); -   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); -   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285     (1988); and -   e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

An in-vivo hydrolysable ester of a compound of the Formula (I) containing a carboxy or a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include C₁₋₆alkoxymethyl esters for example methoxymethyl, C₁₋₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C₁₋₆alkoxycarbonyloxyethyl esters.

An in-vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.

A suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

The compounds of Formula (I) can be prepared by a process comprising a step selected from (a) to (h) as follows, these processes are provided as a further feature of the invention:—

-   (a) Reaction of a compound of formula XXXII with a compound of     formula L²-R^(5′) to form a compound of Formula (I), -    wherein X¹ is selected from -    L¹ is a displaceable group; and -    H—R^(5′) is selected from: -   (b) Reaction of a compound of formula XXXIII with a compound of     formula H—R^(5″) to form a compound of Formula (I), -    wherein X² is selected from: -    L² is a displaceable group and R^(7a) is selected from the     definition of R⁷ or R²² above, and -    L²-R^(5″) is selected from: L²-B—R⁸, L²-J-K—R⁸ and L²-R²¹ -   c) For compounds of Formula (I) wherein R³ is a group of Formula     (IIa), (IIb), (IIc) or (IId) and R⁷ is other than part of a     heterocyclic ring or hydrogen, reaction of a compound of Formula (I)     wherein R³ is a group of Formula (IIa), (IIb), (IIc) or (IId) and R⁷     is hydrogen with a group of formula L³-R^(7a), wherein R^(7a) is as     defined above for R⁷ with the exclusion of hydrogen and L³ is a     displaceable group; -   d) For compounds of Formula (I) wherein R³ is a group of Formula     (IIe) or (IIf) and R²¹ is other than hydrogen, reaction of a     compound of Formula (I) wherein R³ is a group of Formula (IIe) or     (IIf) and R²¹ is hydrogen with a group of formula L⁴-R^(21a),     wherein R^(21a) is as defined above for R²¹ with the exclusion of     hydrogen and L⁴ is a displaceable group; -   e) For compounds of Formula (I) wherein R³ is a group of Formula     (IIe) or (IIf) and R²² is other than hydrogen, reaction of a     compound of Formula (I) wherein R³ is a group of Formula (IIe) or     (IIf) and R²² is hydrogen with a group of formula L⁵-R^(22a),     wherein R^(22a) is as defined above for R²² with the exclusion of     hydrogen and L⁵ is a displaceable group;     -   (f) For compounds of Formula (I) wherein R³ is a group of         Formula (IIc) or (IId) and the group -    together forms an optionally substituted nitrogen-containing     heterocyclic ring containing 47 carbons atoms, reaction of a     compound of Formula XXXIVa or XXXIVb, with a compound of Formula     L⁶-K—R⁸, wherein L⁶ is a displaceable group -   (g) For compounds of Formula (I) wherein R³ is a group of Formula     (IIc) or (IId), reaction of a compound of Formula XXXVa or XXXVb,     with a compound of Formula L⁷-K″—R⁸, wherein L⁷ is a displaceable     group, and wherein the groups K′ and K″ comprise groups which when     reacted together form K, -   (h) reaction of a compound of Formula XXXVI with an electrophillic     compound of the formula L⁸-R⁵, wherein L⁸ is a displaceable group     and thereafter if necessary: -   i) converting a compound of the Formula (I) into another compound of     the Formula (I); -   ii) removing any protecting groups; -   iii) forming a salt, pro-drug or solvate.

Specific reaction conditions for the above reations are as follows:

Process a) Compounds of formula XXXII and H—R^(5′) can be coupled together in the presence of an organic base (such as DIPEA [di-isopropylethylamine]) or an inorganic base (such as potassium carbonate) base, in a suitable solvent such as DMA or DMF, at a temperature from room temperature and 120° C. Suitable displaceable groups include: a halide, such as chloro, or a methane sulphonate or toluene sulphonate;

Process b) Compounds of XXXIII and L²-R^(5″) can be coupled together in the presence of an organic base (such as DIPEA) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMA or DMF, at a temperature from room temperature to 120° C. Suitable displaceable groups include: a halide, such as chloro, or a methane sulphonate or toluene sulphonate,

alternatively if L² is a hydroxy group then the L²-R^(5″); can be reacted with a compound of formula XXXIII under Mitsunobu reaction conditions;

Process c, d, e and f) Reaction conditions to facilitate these reactions can be using

(i) alkylation reaction conditions or (ii) acylation reaction conditions: Examples of said conditions include:

-   -   (i) alkylation reaction conditions—the presence of an organic         base (such as DIPEA) or an inorganic base (such as potassium         carbonate), in a suitable solvent such as DMF, DMA, DCM, at a         temperature from room temperature to 120° C. Suitable         displaceable groups include: a halide, such as chloro, methane         sulphonate or toluene sulphonate;     -   (ii) acylation reaction conditions—presence of organic base,         such as triethylamine, temperature 0° C. to 50-60° C. in a         suitable solvent such as DCM. Suitable displaceable groups         include an acylchloride or an acid anhydride,         Process g) The skilled man would be familiar with a variety of         reaction conditions and values for K′ and K″, which when reacted         together would form the group K, examples of said conditions and         values for K′ and K″ include:     -   (i.) For compounds of Formula (I) where K is         —(CH₂)_(s1)—N(R⁹)C(O)—(CH₂)_(s2)— these can be prepared by         reacting a compound where K′ is —(CH₂)_(s1)—N(R⁹)H with a         carboxylic acid for formula HOOC—(CH₂)_(s2)—R⁸ to form the         amide. Coupling of amino groups with carboxylic acids are well         known in the art and can be facilitated by a number of chemical         reactions using an appropriate coupling reagent. For example a         carbodiimide coupling reaction can be performed with EDCl in the         presence of DMAP in a suitable solvent such as DCM, chloroform         or DMF at room temperature;     -   (ii.) For compounds of Formula (I) where K is         —(CH₂)_(s1)—C(O)N(R⁹)—(CH₂)_(s2)— these can be prepared by         reacting a compound where K′ is —(CH₂)_(s1)—COOH with an amine         of the HN(R⁹)—(CH₂)_(s2)—R⁸ to form the amide. Methodology is         identical to processes described in (i) above in this section;     -   (iii.) For compounds of Formula (I) where K is         —(CH₂)_(s1)—N(R⁹)C(O)O—(CH₂)_(s2)— these can be prepared by         reacting a compound where K′ is —(CH₂)_(s1)—N(R⁹)H with a         chloroformate of formula ClC(O)O—(CH₂)_(s2)R⁸ in a suitable         solvent, such as DCM or chloroform, in the presence of a base,         such as N-methylmorpholine, pyridine or triethylamine, at a         temperature between −10° C. and 0° C.;     -   (iv.) For compounds of Formula (I) where K is         —(CH₂)_(s1)—OC(O)N(R⁹—(CH₂)_(s2)— these can be prepared by         reacting a compound where K′ is —(CH₂)_(s1)—OC(O)Cl with a         compound of formula HN(R⁹)—(CH₂)_(s2)—R⁸. Methodology is         identical to processes described in (iii) above in this section;     -   (v.) For compounds of Formula (I) where K is         —(CH₂)_(s1)—N(R⁹)S(O₂)—(CH₂)_(s2)— these can be prepared by         reacting a compound where K′ is —(CH₂)_(s1)—N(R⁹)H with a         sulphonyl chloride of formula ClS(O₂)—(CH₂)_(s2)—R⁸ in the         presence of a base, such as triethylamine or pyridine, in a         suitable solvent such as chloroform or DCM at a temperature         between 0° C. and room temperature;     -   (vi.) For compounds of Formula (I) where K is         —(CH₂)_(s1)—S(O₂)N(R⁹)—(CH₂)_(s2)— these can be prepared by         reacting a compound where K′ is —(CH₂)_(s1)—S(O2)Cl with a         compound of HN(R⁹)—(CH₂)_(s2)—R⁸. Methodology is identical to         processes described in (v) above in this section     -   (vii.) For compounds of Formula (I) where K is         —(CH₂)_(s1)—N(R⁹)—(CH₂)_(s2)— these can be prepared by reacting         a compound where K′ is —(CH₂)_(s1)-L¹¹ with a compound of         formula HN(R⁹)—(CH₂)_(s2)—R⁸, wherein L¹¹ is a displaceable         group. This reaction can be performed in the presence of an         organic base (such as DIPEA) or an inorganic base (such as         potassium carbonate), in a suitable solvent such as DMA or DMF,         at a temperature from room temperature to 120° C. Suitable         displaceable groups include: a halide, such as chloro, or a         methane sulphonate or toluene sulphonate. Compounds can also be         prepared by reacting a compound wherein K′ is —(CH₂)_(s1)—N(R⁹)H         with a compound of formula L¹¹-(CH₂)_(s2)—R⁸, under identical         conditions.     -   (viii.) For compounds of Formula (I) where K is         —(CH₂)_(s1)—O—(CH₂)_(s2)— these can be prepared by reacting a         compound where K′ is —(CH₂)_(s1)—OH with a compound of formula         L¹²-(CH₂)_(s2)—R⁸, wherein L¹² is a displaceable group. This         reaction can be performed in the presence of an organic base         (such as potassium t-butoxide) or an inorganic base (such as         sodium hydride), in a suitable solvent such as DMA or DMF, at a         temperature from room temperature and 120° C. Suitable         displaceable groups include: a halide, such as bromo, or a         methane sulphonate or toluene sulphonate. Compounds can also be         prepared by reacting a compound wherein K′ is —(CH₂)_(s1)-L¹²         with a compound of formula HO—(CH₂)_(s2)—R⁸, under identical         conditions.     -   (ix.) For compounds of Formula (I) where K is         —(CH₂)_(s1)—C(O)—(CH₂)_(s2)— these can be prepared by reacting a         compound where K′ is —(CH₂)_(s1)—C(O)-L¹³ with a Grignard         reagent of formula BrMg(CH₂)_(s2)—R⁸, wherein L¹³ is a         displaceable group. This reaction can be performed in a         non-polar solvent such as THF or diethylether at a temperature         between room temperature and the boiling point of the solvent.         Suitable displaceable groups include: a halide, such as bromo,         or a methane sulphonate or toluene sulphonate. Compounds can         also be prepared by reacting a compound wherein K′ is         —(CH₂)_(s1)—MgBr with a compound of formula         L¹³-C(O)—(CH₂)_(s2)—R⁸, under identical conditions.

Process h) reaction of a compound of Formula XXXVI with a compound of the formula L⁸-R⁵, can be performed under Friedel Craft conditions, for example in the presence of diethylaluminium chloride in a suitable solvent, such as DCM, in an inert atmosphere such as nitrogen, at a temperature between room temperature and the boiling point of the solvent or under Mannich conditions, for example, formaldehyde and a primary or secondary amine in acetic acid, in an inert atmosphere such as nitrogen at a temperature between room temperature and 100° C. It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of Formula (I) may involve, at an appropriate stage, the addition and subsequent removal of one or more protecting groups.

The protection and de-protection of functional groups is described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The de-protection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The de-protection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

Experimental

General Reaction Schemes

Pyrazoles, such as 3 can be synthesised in two steps (Scheme a):

-   (1) by the reaction of a lactone with the appropriate ester using a     Claisen condensation to form a compound of formula 2, under     conditions of an inert atmosphere, such as argon, at a temperature     of about 0° C. in a suitable solvent such as TBH. -   (2) followed by cyclization of a compound of formula 2 with     hydrazine to form the pyrazole 3, at a room temperature in a     suitable solvent such as ethanol.

The pyrazole 3 can undergo a selective alkylation reaction with a compound of formula 4, under conditions of an inert atmosphere, such as argon, in the presence of a suitable base, such as potassium carbonate in the a suitable solvent such as DMA at a temperature of about 90° C., to form a compound of formula 5. Then the amine 6 can be prepared from a compound of formula 5 and phthalimide using a Mitsunobu reaction with an activating agent such as diethyldiazocarboxylate (DEAD), diisopropyldiazocarboxylate or the like with triphenylphosphine, tri-butylphosphine and the like, in an inert solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof, followec by deprotection with hydrazine to give the (Scheme b).

A suitable pyrazole 6 can be converted to a compound of formula 10 by incorporation of a suitable protecting group (P) to form a compound of formula 7, followed by a Mitsunobu reaction with a suitable alcohol 8 to form a compound of formula 9, followed by deprotection.

EXAMPLES

The invention will now be illustrated with the following non-limiting Examples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration;

(ii) operations were carried out at room temperature, that is in the range 18-25° C. and under an atmosphere of an inert gas such as argon or nitrogen;

(iii) yields are given for illustration only and are not necessarily the maximum attainable;

(iv) the structures of the end-products of the Formula (I) were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet, quin, quintet;

(v) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), high-performance liquid chromatography (HPLC), infra-red (IR) or NMR analysis;

(vi) chromatography was performed on silica (Merck Keiselgel: Art.9385);

(vii) isolute™ refers to silica (SiO₂) based columns with irregular particles with an average size of 50 μm with nominal 60 Å porosity [Source: Jones Chromatography, Ltd., Glamorgan, Wales, United Kingdom].

Abbreviations

-   boc t-butoxycarbonyl -   DCC 1,3-dicyclohexylcarbodiimide -   DEAD diethylazodicarboxylate -   DMA dimethylacetamide -   DMAP 4-dimethylaminopyridine -   DMSO dimethyl sulphoxide -   DMF dimethylformamide -   DNS 2,4-dinitrobenzenesulphonyl -   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride -   HOBt 1-hydroxybenzotriazole -   LHMDS lithium bis(trimethylsilyl)amide -   THF tetrahydrofuran

Example 1 2-[3-(2,2-dimethyl-3-oxo-3-pyrrolidin-1-ylpropoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-(2-pyridin-4-ylethyl)ethanamine

A solution of AR1 (123 mg; 0.17 mmol) in CH₂Cl₂ (3 ml) was treated dropwise with propylamine (140 ul; 1.7 mmol). The mixture was stirred at room temperature for 1 h and then purified directly by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (50 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) to give Example 1 as a beige solid (83 mg).

Yield: 100%

¹H NMR spectrum (DMSO d₆): 1.27 (s, 6H); 1.75 (m, 4H); 2.3 (s, 6H); 2.55-2.95 (m, 8H); 3.5 (m, 4H); 4.18 (s, 2H); 7.03 (s, 1H); 7.10 (s, 2H); 7.2 (d, 2H); 8.44 (d, 2H), 11.9 (s br, 1H).

MS-ESI: 490 [M+H]⁺

The starting material AR1 was prepared as follows:—

A solution of methyl 3,5-dimethylbenzoate (25 g; 152 mmol) and butyrolactone (40 ml; 520 mmol) in THF (300 ml) under argon was cooled to 0° C. and treated dropwise with LHMDS (200 ml; 200 mmol; 1M in hexanes). The mixture was stirred and allowed to warm to room temperature overnight. The THF was evaporated. The residue was taken up in Et₂O and the organic phase was washed with sat. aq. NaHCO₃, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/hexanes (20 to 40% EtOAc) to give an oil which slowly crystallised to give 2 as a white solid (9.2 g). During the chromatography, the starting material methyl 3,5-dimethylbenzoate (12.4 g) was recovered.

Yield: 55% based on recovered methyl 3,5-dimethylbenzoate.

¹H NMR spectrum (CDCl₃): 2.39 (s, 6H); 2.5 (m, 1H); 2.82 (m, 1H); 4.41 (m, 1H); 4.51 (m, 2H); 7.25 (s, 1H); 7.65 (s, 2H).

MS-ESI: 219 [M+H]⁺

Compound 2 (7.43 g; 34 mmol) was dissolved in EtOH (200 ml) and hydrazine hydrate (17.2 ml; 354 mmol) was added. The mixture was stirred for 30 min. The solvent was evaporated and the residue was triturated with pentane to give 3 as a white solid (7.05 g).

Yield: 90%

¹H NMR spectrum (DMSO d₆): 2.32 (s, 6H); 2.58 (t, 2H); 3.50 (t, 2H); 4.8 (br s, 1H); 7.01 (s, 1H); 7.14 (s, 2H); 9.5 (br s, 1H).

MS-ESI: 233 [M+H]⁺

A mixture of 3 (4.26 g; 18.4 mmol) and 4 (4.51 g; 19.3 mmol) in DMA (40 ml) under argon was treated with K₂CO₃ (5.07 g; 36.7 mmol). The mixture was stirred and heated at 90° C. for 2 h. The mixture was poured into sat. aq. NaHCO₃, extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 100% EtOAc) to give the alcohol 5 as a pale yellow oil (6.56 g).

Yield: 93%

¹H NMR spectrum (DMSO d₆): 1.30 (s, 6H); 1.8 (m, 4H); 2.33 (s, 6H); 2.55 (m, 2H); 3.32 (m, 2H); 3.5 (m, 4H); 4.17 (s, 2H); 4.62 (t, 1H); 7.04 (s, 1H); 7.16 (s, 2H); 11.9 (br s, 1H).

MS-ESI: 386 [M+H]⁺

A mixture of 5 (3.85 g; 10 mmol), phthalimide (1.62 g; 11 mmol) and triphenylphosphine (10.5 g; 40 mmol) in THF (100 ml) at 0° C. under argon was treated with DEAD (6.33 ml; 40 mmol). The mixture was stirred at this temperature for 1 h when water was added. The mixture was extracted with Et₂O and the organic phase was washed with water, brine and dried over MgSO₄.

Evaporation gave a crude solid which, without further purification, was immediately taken up in EtOH (50 ml) and treated with hydrazine hydrate (5 ml; 100 mmol). The mixture was stirred for 1.5 h and then the EtOH was partially evaporated. Addition of CH₂Cl₂ caused precipitation of phthalhydrazide which was filtered and rinsed with CH₂Cl_(2.) The filtrate was evaporated and the residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 8% MeOH) to give 6 as a beige solid (2.34 g).

Yield: 61%

¹H NMR spectrum (DMSO d₆):1.30 (s, 6H); 1.79 (m, 4H); 2.33 (s, 6H); 2.52 (m, 2H); 2.67 (t, 2H); 3.5 (m, 4H); 4.18 (s, 2H); 7.03 (s, 1H); 7.14 (s, 2H); 8.95 (br s, 1H).

MS-ESI: 385 [M+H]⁺

A solution of 6 (200 mg; 0.52 mmol) in CH₂Cl₂ (5 ml) was treated with diisopropylethylamine (135 ul; 0.78 mmol) and cooled to 0° C. A solution of 2,4-dinitrobenzenesulphonyl chloride (153 mg; 0.57 mmol) in CH₂Cl₂ (1 ml) was added dropwise and the mixture was allowed to warm to room temperature for 30 min. The mixture was purified directly by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₁Cl₂ (0 to 50% EtOAc) to give 7 as a cream solid (224 mg).

Yield: 70%

¹H NMR spectrum (DMSO d₆): 1.24 (s, 6H); 1.75 (m, 4H); 2.29 (s, 6H); 2.57 (m, 2H); 3.11 (m, 2H); 3.5 (m, 4H); 4.15 (s, 2H); 7.0 (s, 1H); 7.03 (s, 2H); 8.14 (d, 1H); 8.56 (q, 1H); 8.6 (br s, 1H); 8.83 (d, 1H).

MS-ESI: 615 [M+H]⁺

A mixture of 7 (170 mg; 0.27 mmol), 4-(2-hydroxyethyl)-pyridine (38 mg; 0.3 mmol) and triphenylphosphine (283 mg; 1.08 mmol) in THF (10 ml) at 0° C. under argon was treated with DEAD (170 ul; 1.08 mmol). The mixture was allowed to warm to room temperature for 30 min. when water was added. The mixture was extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl, (0 to 100% EtOAc) AR1 as a white solid (123 mg).

Yield: 63%

¹H NMR spectrum (DMSO d₆): 1.27 (s, 6H); 1.7 (m, 4H); 2.28 (s, 6H); 2.69 (t, 2H); 2.83 (t, 2H); 3.4 (m, 4H); 3.48 (t, 2H); 3.56 (t, 2H); 4.21 (s, 2H); 7.01 (s, 1H); 7.08 (s, 2H); 7.19 (d, 2H); 8.15 (d, 1H); 8.41 (d, 2H); 8.42 (q, 1H); 8.89 (d, 1H).

MS-ESI: 720 [M+H]⁺

Starting material 4 was prepared as follows:—

A mixture of 8 (14.48 g; 80 mmol) and oxalyl bromide (43.2 g; 200 mmol) containing one drop of DMF was heated at 50° C. for 2 h and then cooled. The excess of oxalyl bromide was evaporated and the residue azeotroped with toluene to give crude 9 which was taken up directly in CH₂Cl₂ (25 ml) and cooled to 0° C. Diisopropylethylamine (14 ml; 80 mmol) was added followed by a solution of pyrrolidine (3.3 ml; 40 mmol) in CH₂Cl₂ (30 ml). The mixture was allowed to warm to room temperature overnight and was diluted with CH₂Cl₂, washed with aq. HCl (2N), aq. NaOH (1N), water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (5 to 10% EtOAc) to give 4 as a white solid (6.5 g).

Yield: 70%

¹H NMR spectrum (DMSO d₆): 1.39 (s, 6H); 1.9 (m, 4H); 3.57 (m, 4H); 3.62 (s, 2H)

MS-ESI: 235 [M+H]⁺

Examples 1.1-1.5

The following examples were prepared in a similar manner to Example 1,

the table shows the R group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 1 given above:—

Example 1.1

R AR2 mg; mmol CH₂Cl₂ ml Propylamine μl; mmol Prod. Form Mass mg; Yield MS-ESI

210; 0.28 5 235; 2.86 White solid 111; 77% 504 [M + H]⁺ Chromato. - EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.27(s, 6H); 1.75(m, 4H); 2.31(s, 6H); 2.57-2.63(m, 6H); 2.75(m, 2H); 3.3-3.7(m, 4H); 4.18(s, 2H); 7.03(s, 1H); 7.11(s, 2H); 7.2(d, 2H); 8.44(d, 2H); 11.9(s br, 1H).

Example 1.2

R AR3 mg; mmol CH₂Cl₂ ml Propylamine μl; mmol Prod. Form Mass mg; Yield MS-ESI

120; 0.16 3 135; 163 White solid 60; 73% 504 [M + H]⁺ Chromato. - Ammonia in MeOH(7N)/(CH₂Cl₂ (0 to 10% ammonia in MeOH) ¹H NMR spectrum (DMSO d₆); 1.27(s, 6H); 1.6-1.9(m, 6H); 2.3(s, 6H); 2.55-2.64(m, 6H); 2.7(m, 2H); 3.3-3.6(m, 4H); 4.17(s, 2H); 7.02(s, 1H); 7.12(s, 2H); 7.29(dd, 1H); 7.58(d, 1H); 8.39(d, 1H); 11.9(s br, 1H).

Examples 1.3-1.5 were prepared by a robot. The last two steps were carried out sequentially without isolation of the intermediates AR4, AR5 or AR6.

Example 1.3

R AR4 mg; mmol CH₂Cl₂ ml Ammonia in MeOH(7N) ml Prod. Form Mass mg; Yield MS-ESI

nd*; 0.23 5 0.5 oil 18; 15% 514 [M + H]⁺ Chromato. - LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (0 to 100% H₂O) ¹H NMR spectrum (DMSO d₆): 1.26(s, 6H); 1.74(m, 4H); 2.3(s, 6H); 2.55-2.8(m, 8H); 3.4(m, 4H); 4.16(s, 2H); 7.02(s, 1H); 7.10(s, 2H); 7.36(d, 2H); 7.71(d, 2H); 11.9(s br, 1H).

Example 1.4

R AR5 mg; mmol CH₂Cl₂ ml Ammonia in MeOH(7N) ml Prod. Form Mass mg; Yield MS-ESI

nd*; 0.23 5 0.5 oil 15; 12% 519 [M + H]⁺ Chromato. - LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (0 to 100% H₂O) ¹H NMR spectrum (DMSO d₆): 1.27(s, 6H); 1.74(m, 4H); 2.30(s, 6H); 2.5-2.75(m, 8H); 3.5(m, 4H); 3.71(s, 3H); 4.16(s, 2H); 6.81(d, 2H); 7.02(s, 1H); 7.05(d, 2H); 7.11(s, 2H); 11.9(s br, 1H).

Example 1.5

R AR6 mg; mmol CH₂Cl₂ ml Ammonia in MeOH(7N) ml Prod. Form Mass mg; Yield MS-ESI

nd*; 0.23 5 0.5 oil 23; 18% 549 [M + H]⁺ *nd = not determined Chromato. - LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (0 to 100% H₂O) ¹H NMR spectrum (DMSO d₆): 1.27(s, 6H); 1.77(m, 4H); 2.3(s, 6H); 2.55-2.7(m, 8H); 3.5(m, 4H); 3.68(s, 3H); 3.9(t, 2H); 4.16(s, 2H); 6.81(m, 4H); 7.01(s, 1H); 7.12(s, 2H); 11.9(s br, 1H). Intermediates for Examples 1-1-1.5, AR2-AR6 Respectively

Starting materials AR2-AR6 were prepared as follows, the table showing the reaction conditions and characteristics for each example, corresponding to the description of AR1 given above:—

AR2 7 mg; Alcohol PPh3 THF R mmol mg; mmol mg; mmol ml DEAD μl; mmol Prod. Form Mass mg; Yield % MS-ESI

200; 0.32 55; 0.4 340; 1.3 10 205; 1.3 Yellow solid 216; 90% 734 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc) ¹H NMR spectrum (DMSO d₆): 1.22(s, 6H); 1.6-1.8(m, 4H); 1.84(m, 2H); 2.28(s, 6H); 2.55(m, 2H); 2.69(m, 2H); 3.3-3.5(m, 8H); 4.18(s, 2H); 7.00(s, 1H); 7.07(s, 2H); 7.19(d, 2H); 8.17(d, 1H); 8.43(d, 2H); 8.47(dd, 1H); 8.92(d, 1H); 11.9(s br, 1H).

AR3 7 mg; Alcohol PPh3 THF R mmol mg; mmol mg; mmol ml DEAD μl; mmol Prod. Form Mass mg; Yield % MS-ESI

200; 0.32 55; 0.4 340; 1.3 5 205; 1.3 Yellow solid 122; 51% 734 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc) ¹H NMR spectrum (DMSO d₆): 1.22(s, 6H); 1.5-1.9(m, 4H); 1.84(m, 2H); 2.28(s, 6H); 2.55(m, 2H); 2.68(m, 2H); 3.3-3.5(m, 8H); 4.18(s, 2H); 7.00(s, 1H); 7.07(s, 2H); 7.28(dd, 1H); 7.58(d, 1H); 8.17(d, 1H); 8.40(m, 2H); 8.47(dd, 1H); 8.92(d, 1H); 11.9(s br, 1H).

AR4 7 mg; Alcohol PPh3 R mmol mg; mmol mg; mmol THF ml DTAD mg; mmol Prod. Form Mass mg; Yield % MS-ESI

145; 0.23 38; 0.26 360; 1.38 1 205; 0.9 nd* nd* nd* *not determined: Intermediate used directly in last step of robot run without isolation or purification.

AR5 7 mg; Alcohol R mmol mg; mmol PPh3 mg; mmol THF ml DTAD mg; mmol Prod. Form Mass mg; Yield % MS-ESI

145; 0.23 40; 0.26 360; 1.38 1 205; 0.9 nd* nd* nd*

AR6 7 mg; Alcohol PPh3 THF DTAD R mmol mg; mmol mg; mmol ml mg; mmol Prod. Form Mass mg; Yield % MS-ESI

145; 0.23 47; 0.26 360; 1.38 1 205; 0.9 nd* nd* nd*

Example 2 2-[3-(2,2-dimethyl-3-oxo-3-{pyrrolidin-1-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-(4-pyridin-4-ylbutyl)ethanamine

Dry, gaseous HCl was bubbled through a solution of Ab6 (180 mg; 0.29 mmol) in CH₂Cl₂ (30 ml) until no Ab6 remained. The mixture was treated with iced sat. aq. NaHCO₃, extracted with CH₂Cl₂ and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ammonia in MeOH(7N)/CH₂Cl₂ (0 to 10% ammonia in MeOH) to give Example 2 (114 mg).

Yield: 76%

¹H NMR spectrum (CDCl₃): 1.38 (s, 6H); 1.45 (m, 2H); 1.6 (m, 2H); 1.84 (m, 4H); 2.33 (s, 6H); 2.59 (m, 4H); 2.65 (t, 2H); 2.77 (t, 2H); 3.57; (m, 4H); 4.32 (s, 2H); 7.01 (s, 1H); 7.04 (s, 2H); 7.08 (d, 2H); 8.47 (d, 2H); 11.9 (s br, 1H).

MS-ESI: 518 [M+H]⁺

The starting material Ab6 was prepared as follows:—

A solution of methyl 3,5-dimethylbenzoate (50 g; 300 mmol) in DME (80 ml) was added to a suspension of NaH (26.8 g; 60% in oil; 670 mmol) in DME (80 ml) under argon. The mixture was heated to reflux and a solution of methyl acetate (45 g; 610 mmol) in DME (40 ml) added dropwise. The mixture was heated for a further 4 h under reflux. The mixture was cooled and the excess of NaH destroyed by the dropwise addition of MeOH (40 ml). The mixture was poured into dilute HCl (2N), extracted with Et₂O and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with Et₂O/hexanes (10% Et₂O) to give methyl 4-(3′,5′-dimethylphenyl)acetoacetate as a yellow oil (31 g).

Yield: 50%

¹H NMR spectrum (CDCl₃): This compound exists as a 4/1 mixture of keto (k) and enol (e) forms: 2.36 (s, 6H)(e); 2.38 (s, 6H)(k); 3.76 (s, 3H)(k); 3.81 (s, 3H)(e); 4.03 (s, 2H)(k); 5.65 (s, 1H)(e); 7.11 (s, 1H)(e); 7.27 (s, 1H)(k); 7.4 (s, 2H)(e); 7.56 (s, 2H)(k); 12.48 (s, 1H)(e).

MS-ESI: 207 [M+H]⁺

NaH (2.44 g; 60% in oil; 61 mmol) was added in small portions to a solution of methyl 4-(3′,5′-dimethylphenyl)acetoacetate (9.66 g; 46.9 mmol) in DMF (50 ml) at 0° C. under argon. The mixture was stirred and allowed to warm to room temperature for 30 min. A solution of allyl bromide (4.05 ml; 46.9 mmol) in DMF (5 ml) was added dropwise and the mixture stirred for a further 2 h. The mixture was poured into H₂O, extracted with Et₂O and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with Et₂O/hexanes (0 to 15% Et₂O) to give Ab1 as a pale yellow oil (8.3 g).

Yield: 72%

¹H NMR spectrum (CDCl₃): 2.39 (s, 6H); 2.76 (m, 2H); 3.70 (s, 3H); 4.43 (t, 1H); 5.08 (m, 1H); 5.15 (m, 1H); 5.82 (m, 1H); 7.24 (s, 1H); 7.60 (s, 2H).

MS-ESI: 247 [M+H]⁺

A solution of Ab1 (3.4 g; 13 mmol) in EtOH (30 ml) was treated with hydrazine hydrate (3.9 ml; 78 mmol) and heated under reflux for 3 h. The EtOH was evaporated and the residue triturated with Et₂O. The precipitate was filtered, washed with H₂O and dried to give Ab2 as a white powder (2.8 g).

Yield: 95%

¹H NMR spectrum (CDCl₃+TFAD): 2.42 (s, 6H); 3.32 (d, 2H); 5.11 (d, 1H); 5.19 (d, 1H); 5.97 (m, 1H); 7.16 (s, 2H); 7.24 (s, 1H); 10.95 (s br 1H).

MS-ESI: 229 [M+H]⁺

A mixture of Ab2 (2.1 g; 9.2 mmol) and 4 (2.15 g; 9.2 mmol) in DMA (30 ml) under argon was treated with K₂CO₃ (2.54 g; 18.4 mmol). The mixture was stirred and heated at 80° C. for 2 h. The mixture was poured into sat. aq. NaHCO₃, extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (50 to 100% EtOAc) to give Ab3 as a pale yellow solid (2.8 g).

Yield: 80%

¹H NMR spectrum (CDCl₃): 1.35 (s, 6H); 1.8 (m, 4H); 2.32 (s, 6H); 3.14 (m, 2H); 3.55 (m, 4H); 4.18 (s, 2H); 4.97 (m, 2H); 5.89 (m, 1H); 7.02 (s, 1H); 7.03 (s, 2H); 8.9 (br s, 1H).

MS-ESI: 382 [M+H]⁺

A mixture of Ab3 (2.59 g; 6.8 mmol) and BOC)₂O (7.4 g; 34 mmol) in CH₃CN (80 ml) was treated with Et₃N (1.9 ml; 13.6 mmol). The mixture was heated at 80° C. for 3 h. The solvent was evaporated, the mixture was poured into sat. aq. NaHCO₃, extracted with Et₂O and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 25% EtOAc) to give Ab4 as a white solid (2.51 g).

Yield: 76%

¹H NMR spectrum (CDCl₃): 1.18 (s, 9H); 1.34 (s, 6H); 1.8 (m, 4H); 2.3 (s, 6H); 2.85 (m, 2H); 3.54 (m, 4H); 4.43 (s, 2H); 4.87 (m, 2H); 5.73 (m, 1H); 6.8 (s, 2H); 6.98 (s, 1H).

MS-ESI: 482 [M+H]⁺

4-Methyl-morphololine-N-oxide (1.6 ml; 60% solution in H₂O) was added to a solution of Ab4 (2.21 g; 4.6 mmol) in THF (100 ml) and H₂O (30 ml). The mixture was cooled to 0° C. and a solution of OsO₄ (92 mg; 0.36 mmol) in t-BuOH (1.8 ml) was added dropwise. The mixture was allowed to warm to room temperature for 6 h. The reaction was quenched by the addition of aq. Na₂S₂O₅ (1.75 g) in H₂O (50 ml). The THF was evaporated and the mixture extracted with EtOAc. The organic phase was washed with water, brine and dried over MgSO₄. The residue (2.21 g) was taken up in THF (100 ml) and H₂O (30 ml) and treated with NaIO₄. The mixture was stirred overnight. The THF was evaporated and the mixture extracted with EtOAc. The organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 50% EtOAc) to give Ab5 as a buff solid (1.63 g).

Yield: 73%

¹H NMR spectrum (CDCl₃): 1.21 (s, 9H); 1.34 (s, 6H); 1.9 (m, 4H); 2.32 (s, 6H); 3.23 (d, 2H); 3.55 (m, 4H); 4.47 (s, 2H); 6.8 (s, 2H); 7.01 (s, 1H); 9.56 (d, 1H).

MS-ESI: 484 [M+H]⁺

A solution of Ab5 (360 mg; 0.74 mmol) and 4-(4-aminobutyl)-pyridine (123 mg; 0.82 mmol) in MeOH (6 ml) was treated with NaBH₃CN (52 mg; 0.82 mmol). The mixture was cooled to 0° C. and acetic acid (45 μl; 0.82 mmol) was added. The mixture was allowed to warm to room temperature for 2 h and evaporated. The residue was treated with aq. K₂CO₃ (10%) and the mixture extracted with EtOAc. The organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with EtOAc and then increasingly polar mixtures of MeOH/CH₂Cl₂ (0 to 5% MeOH) to give Ab6 as an oil (180 mg).

Yield: 40%

¹H NMR spectrum (CDCl₃): 1.20 (s, 9H); 1.37 (s, 6H); 1.61 (m, 2H); 1.87 (m, 6H); 2.31 (s, 6H); 2.48 (m, 2H); 2.62 (m, 4H); 2.76 (m, 2H); 3.57 (m, 4H); 4.45 (s, 2H); 6.8 (s, 2H); 7.0 (s, 1H); 7.08 (d, 2H); 8.47 (d, 2H).

MS-ESI: 618 [M+H]⁺

Example 3 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-(4-pyridin-4-ylbutyl)-ethanamine

A solution of BR1 (322 mg; 0.41 mmol) in CH₂Cl₂ (5 ml) was treated dropwise with propylamine (340 μl; 4.1 mmol). The mixture was stirred at room temperature for 1 h and then purified directly by flash chromatography eluting with increasingly polar mixtures of MeOH/CH₂Cl₂ (0 to 10% MeOH) to give Example 3 as a white solid (219 mg).

Yield: 98%

¹H NMR spectrum (DMSO d₆): 1.25 (s, 6H); 1.43 (m, 6H); 1.61 (m, 6H); 2.3 (s, 6H); 2.59 (m, 4H); 2.65 (m, 2H); 2.75 (m, 2H); 4.16 (s, 2H); 4.57 (s, 2H); 7.02 (s, 1H); 7.11 (s, 2H); 7.21 (d, 2H); 8.44 (m, 2H); 11.8 (s br 1H).

MS-ESI: 544 [M+H]⁺

Starting material BR1 was prepared as follows:—

A mixture of 3 (4.64 g; 20 mmol) and Ba (5.72 g; 22 mmol) in DMA (50 ml) under argon was treated with K₂CO₃ (5.52 g; 40 mmol). The mixture was stirred and heated at 70° C. for 6 h. The mixture was poured into sat. aq. NaHCO₃, extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 50% EtOAc) to give the alcohol Bb as a pale yellow oil (7.58 g).

Yield: 92%

¹H NMR spectrum (DMSO d₆): 1.25 (s, 6H); 1.42 (m, 4H); 1.62 (m, 4H); 2.31 (s, 6H); 2.53 (m, 2H); 3.46 (m, 2H); 4.14 (s, 2H); 4.58 (s, 2H); 4.61 (t, 1H); 7.02 (s, 1H); 7.14 (s, 2H); 11.9 (br s, 1H).

MS-ESI: 412 [M+H]⁺

A mixture of Bb (3.29 g; 8 mmol), phthalimide (2.35 g; 16 mmol) and triphenylphosphine (12.5 g; 48 mmol) in THF (50 ml) was cooled to −20° C. under argon and treated dropwise with DEAD (7.6 ml; 48 mmol). The mixture was allowed to warm to 10° C. for 1 h when water was added and the TBH evaporated. The mixture was extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO₄.

Evaporation gave a crude solid which, without further purification, was immediately taken up in EtOH (200 ml) and treated with hydrazine hydrate (16 ml; 320 mmol). The mixture was stirred for 2 h and then the EtOH was partially evaporated. Addition of CH₂Cl₂ caused precipitation of phthalhydrazide which was filtered and rinsed with CH₂Cl_(2.) The filtrate was evaporated and the residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH) to give Bc as a pale beige solid (2.53 g).

Yield: 77%

¹H NMR spectrum (DMSO d₆): 1.25 (s, 6H); 1.42 (m, 4H); 1.62 (m, 4H); 2.31 (s, 6H); 2.46 (m, 2H); 2.65 (t, 2H); 4.15 (s, 2H); 4.58 (m, 2H); 7.01 (s, 1H); 7.12 (s, 2H); 11.8 (s br 1H).

MS-ESI: 411 [M+H]⁺

A solution of Bc (1.43 g; 3.48 mmol) in CH₂Cl₂ (30 ml) was treated with diisopropylethylamine (910 μl; 5.22 mmol) and cooled to 0° C. A solution of 2,4-dinitrobenzenesulphonyl chloride (1.02 g; 3.84 mmol) in CH₂Cl₂ (10 ml) was added dropwise and the mixture was allowed to warm to room temperature for 30 min. The mixture was poured into sat. aq. NaHCO₃, extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 20% EtOAc) to give Bd as a cream solid (1.1 g).

Yield: 50%

¹H NMR spectrum (DMSO d₆): 1.22 (s, 6H); 1.41 (m, 4H); 1.59 (s, 4H); 2.3 (s, 6H); 2.57 (m, 2H); 3.11 (m, 2H); 4.12 (s, 2H); 4.55 (s, 2H); 7.0 (s, 1H); 7.03 (s, 2H); 8.17 (d, 1H); 8.59 (m, 2H); 8.83 (d, 1H); 11.8 (s br 1H).

MS-ESI: 641 [M+H]⁺

A mixture of Bd (300 mg; 0.43 mmol), 4-(4-hydroxybutyl)-pyridine (84 mg; 0.56 mmol) and triphenylphosphine (495 mg; 1.87 mmol) in THF (10 ml) at 0° C. under argon was treated dropwise with DEAD (300 μl; 1.87 mmol). The mixture was allowed to warm to room temperature for 30 min. when water was added. The THF was evaporated, the mixture extracted with EtOAc and the organic phase washed with water, brine and dried over MgSO₄.

The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 100% EtOAc) BR1 as a white solid (322 mg).

Yield: 89%

¹H NMR spectrum (DMSO d₆): 1.24 (s, 6H); 1.38 (m, 4H); 1.54 (m, 8H); 2.29 (s, 6H); 2.57 (m, 2H); 2.64 (m, 2H); 3.36 (m, 4H); 4.18 (s, 2H); 4.52 (m, 2H); 7.02 (s, 1H); 7.08 (s, 2H); 7.16 (d, 2H); 8.20 (d, 1H); 8.41 (d, 2H); 8.47 (dd, 1H); 8.91 (d, 1H); 11.8 (s br 1H).

MS-ESI: 774 [M+H]⁺

Starting material Ba was prepared as follows:—

A mixture of 8 (14.48 g; 80 mmol) and oxalyl bromide (43.2 g; 200 mmol) containing one drop of DMF was heated at 50° C. for 2 h and then cooled. The excess of oxalyl bromide was evaporated and the residue azeotroped with toluene to give crude 9 which was taken up in CH₂Cl₂ (25 ml) and cooled to 0° C. Diisopropylethylamine (14 ml; 80 mmol) was added followed by 2.2.1-azabicycloheptane hydrochloride (5.34 g; 40 mmol). The mixture was allowed to warm to room temperature overnight and was diluted with CH₂Cl₂, washed with aq. HCl (2N), aq. NaOH (1N), water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with CH₂Cl₂ to give Ba as a white solid (7.4 g).

Yield: 71%

¹H NMR spectrum (CDCl₃): 1.36 (s, 6H); 1.49 (m, 4H); 1.82 (m, 4H); 3.59 (s, 2H); 4.61 (s, 2H).

Examples 3.1-3.5

The following examples were prepared in a similar manner to Example 3,

the table shows the R group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 3 given above:—

Example 3.1

BR2 mg; CH₂Cl₂ Propylamine Mass mg; MS- R mmol ml μl; mmol Yield ESI

292; 0.39 5 320; 3.9 161; 80% 516 [M + H]+ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.25 (s, 6H); 1.41 (m, 4H); 1.6 (m, 4H); 2.29 (s, 6H); 2.55 (m, 2H); 2.71 (m, 4H); 2.81 (m, 2H); 4.15 (s, 2H); 4.56 (s, 2H); 7.02 (s, 1H); 7.10 (s, 2H); 7.2 (d, 2H); 8.43 (dd, 2H); 11.7 (s br 1H).

Example 3.2

BR3 mg; CH₂Cl₂ Propylamine Mass mg; MS- R mmol ml μl; mmol Yield ESI

123; 0.17 3 140; 1.67 58; 68% 506 [M + H]+ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.25 (s, 6H); 1.42 (m, 4H); 1.61 (m, 4H); 2.3 (s, 6H); 2.46 (m, 2H); 2.64 (m, 2H); 2.88 (m, 2H); 4.15 (s, 2H); 4.19 (t, 2H); 4.57 (s, 2H); 7.01 (s, 1H); 7.09 (s, 2H); 7.92 (s, 1H); 8.42 (s, 1H); 11.9 (s br, 1H).

Example 3.3

BR4 mg; CH₂Cl₂ Propylamine Mass mg; MS- R mmol ml μl; mmol Yield ESI

96; 0.12 3 140; 1.67 50; 72% 579 [M + H]+ Chromato. - EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.26 (s, 6H); 1.44 (m, 4H); 1.61 (m, 6H); 1.97 (s, 3H) 2.25 (s, 2H); 2.32 (s, 6H); 2.4-2.85 (m, 14H); 4.16 (s, 2H); 4.58 (s, 2H); 7.04 (s, 1H); 7.11 (s, 2H); 11.8 (s, 1H).

Example 3.4

BR5 mg; CH₂Cl₂ Propylamine Mass mg; MS- R mmol ml μl; mmol Yield ESI

167; 0.22 3 180; 2.2 30; 25% 538 [M + H]⁺ Chromato. - EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.26 (s, 6H); 1.44 (m, 4H); 1.57 (m, 2H); 1.62 (m, 4H); 2.27 (m, 6H); 2.32 (s, 6H); 2.5-2.85 (m, 6H); 3.52 (s, 4H); 4.16 (s, 2H); 4.58 (s, 2H); 7.03 (s, 1H); 7.12 (s, 2H); 11.8 (s, 1H).

Example 3.5

BR6 mg; CH₂Cl₂ Propylamine Mass mg; MS- R mmol ml μl; mmol Yield ESI

194; 0.24 3 195; 2.4 93; 66% 586 [M + H]⁺ Chromato. - EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.26 (s, 6H); 1.44 (m, 4H); 1.55 (m, 2H); 1.61 (m, 4H); 2.32 (s, 6H); 2.4-2.85 (m, 8H); 2.82 (s, 4H); 3.04 (m, 4H); 4.16 (s, 2H); 4.58 (s, 2H); 7.03 (s, 1H); 7.12 (s, 2H); 11.8 (s, 1H). Intermediates for Examples 3.1-3.5, BR2-BR6 Respectively

Starting materials BR2-6 were prepared as follows, the table showing the reaction conditions and characteristics for each example, corresponding to the description of Example 3 given above:—

BR2 Bd mg; Alcohol PPh₃ mg; THF DEAD Mass mg; MS- R mmol mg; mmol mmol ml μl; mmol Yield ESI

300; 0.47 70; 0.56 495; 1.87 10 290; 1.84 292; 83% 746 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc)

BR3 Bd mg; Alcohol PPh₃ mg; THF DEAD Mass mg; MS- R mmol mg; mmol mmol ml μl; mmol Yield ESI

150; 0.23 32; 0.28 362; 1.38 5 145; 0.92 123; 72% 736 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc)

BR4 Bd mg; Alcohol PPh₃ mg; THF DEAD Mass mg; MS- R mmol mg; mmol mmol ml μl; mmol Yield ESI

150; 0.23 53; 0.28 362; 1.38 5 200; 1.26 96; 51% 809 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH)

BR5 Bd mg; Alcohol PPh₃ mg; THF DEAD Mass mg; MS- R mmol mg; mmol mmol ml μl; mmol Yield ESI

200; 0.31 54; 0.37 490; 1.86 5 270; 1.72 167; 70% 768 [M + H]⁺ Chromato. - EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH)

BR6 Bd mg; Alcohol PPh₃ mg; THF DEAD Mass mg; MS- R mmol mg; mmol mmol ml μl; mmol Yield ESI

200; 0.31 72; 0.37 490; 1.86 5 270; 1.72 194; 77% 816 [M + H]⁺ Chromato. - EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH).

Example 4 2-[3-(2,2-dimethyl-3-oxo-3-azabicyclo[2.2.1]heptan-7-ylpropoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine

A solution of partially purified* Cg17 (4.2 g; from 2.3 mmol of Cf) in CH₂Cl₂ (30 ml) under nitrogen was treated dropwise with n-propylamine (1.36 ml; 23 mmol) at room temperature. The mixture was stirred at room temperature for 2 h, the solvents evaporated and the residue purified directly by flash chromatography eluting with increasingly polar mixtures of EtOAc and then MeOH/CH₂Cl₂ (0 to 15% MeOH) to give Example 4 as a beige solid (768 mg). *Contains some Ph₃PO

Yield: 59% for last two steps.

¹H NMR spectrum (DMSO d₆): 1.13 (d, 3H); 1.25 (s, 6H); 1.42 (m, 4H); 1.60 (m, 4H); 2.3 (s, 6H); 2.55-2.95 (m, 7H); 4.14 (s, 2H); 4.57 (s, 2H); 5.94 (s, 2H); 6.55 (d, 1H); 6.69 (s, 1H); 6.76 (d, 1H); 7.03 (s, 1H); 7.04 (s, 2H); 11.8 (s br 1H).

MS-ESI: 573 [M+H]⁺

Starting materials Ce, Cf and CR17 were prepared as follows:—

A solution of methyl 3,5-dimethylbenzoate (148 g; 0.9 mol) and 3S-methylbutyrolactone (90 g; 0.9 mol) in THF (2.4 l) under argon was cooled to 0° C. and treated dropwise rapidly with LHMDS (1.35 l; 1.35 mol; 1M in hexanes). The mixture was stirred for 2 h while the temperature was maintained below 10° C. The mixture was poured into dilute HCl (2N, 800 ml) at 0° C. Further dilute HCl (2N) was added until the pH reached 1.6. The THF was evaporated and the residual aqueous phase was extracted with EtOAc. The organic phase was washed with sat. aq. NaHCO₃, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/hexanes (10 to 15% EtOAc) to give Ca as a colourless oil (127.7 g).

Yield: 61%.

¹H NMR spectrum (DMSO d₆): 1.09 (td, 3H); 2.36 (s, 6H); 3.05 (m, 1H); 3.93 (t, 1H); 4.50 (t, 1H); 4.78 (d, 1H); 7.36 (s, 1H); 7.67 (s, 2H).

MS-ESI: 233 [M+H]⁺

Compound Ca (127.5 g; 0.55 mol) was dissolved in EtOH (2.0 l) and hydrazine hydrate (27 ml; 0.55 mol) was added. The mixture was stirred overnight at room temperature. Dilute HCl (12N; 12 ml) was added and the mixture stirred for a further 1 h. The precipitate was filtered to give Cb as a white solid (63 g). Crystallisation from the mother liquors yielded further batches of Cb (29 g).

Yield: 68%

¹H NMR spectrum (DMSO d₆): 1.15 (d, 3H); 2.23 (s, 6H); 2.77 (m, 1H); 3.53 (d, 2H); 4.77 (br s, 1H); 7.01 (s, 1H); 7.04 (s, 2H); 9.5 (br s, 1H).

MS-ESI: 247 [M+H]⁺

A mixture of Cb (50 g; 0.20 mol) and Ba (60 g; 0.23 mol) in DMA (350 ml) under argon was treated with K₂CO₃ (56 g; 0.41 mol). The mixture was stirred and heated at 80° C. overnight. The mixture was cooled and poured into a stirred mixture of sat. aq. NAHCO₃/H₂O (1:2.5). The precipitate was filtered, washed abundantly with water and dried, to give the alcohol Cc as a pale beige solid. (84.5 g).

Yield: 99%

¹H NMR spectrum (DMSO d₆): 1.12 (d, 3H); 1.25 (s, 6H); 1.42 (m, 4H); 1.62 (m, 4H); 2.31 (s, 6H); 2.75 (m, 1H); 3.46 (m, 2H); 4.14 (m, 2H); 4.51 (br s, 1H); 4.58 (m, 2H); 7.03 (s, 1H); 7.06 (s, 2H); 11.9 (br s, 1H).

MS-ESI: 426 [M+H]⁺

A solution of Cc (42 g; 0.1 mol) in CH₂Cl₂ (800 ml) under argon was treated with acetonitrile (3 l) and DMAP (250 mg; cat.). The mixture was stirred and cooled to 0° C. and a solution of BOCOBOC (24 g; 0.11 mol) in acetonitrile (100 ML) was added slowly, dropwise. The mixture was allowed to warm to room temperature until no Cc remained (˜1 day) and was poured into water (2 l) and stirred for 4 h. The organic solvents were evaporated. The mixture was extracted with CH₂Cl₂ and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (20 to 50% EtOAc) to give Cd as a colourless foam (25.5 g).

Yield: 50%

¹H NMR spectrum (DMSO d₆): 1.02 (d, 3H); 1.16 (s, 9H); 1.270 (s, 6H); 1.44 (m, 4H); 1.62 (m, 4H); 2.29 (s, 6H); 2.33 (m, 1H); 3.38 (m, 2H); 4.23 (m, 2H); 4.54 (m, 1H); 4.59 (s, 2H); 6.89 (s, 1H); 7.05 (s, 2H).

MS-ESI: 526 [M+H]⁺

A solution of Cd (50.9 g; 97 mmol), phthalimide (17 g; 116 mmol) and triphenyl phosphine (38 g; 145 mmol) in THF (1 l) under argon was cooled to 0° C. and treated rapidly, portionwise with DTAD (33.3 g; 145 mmol). The mixture was allowed to warm to room temperature for 2 h 30 min. Water (500 ml) was added to the mixture and the organic solvent evaporated. The mixture was extracted with CH₂Cl₂ and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 15% EtOAc) to give a cream foam (48.4 g) which was dissolved in EtOH (1.5 l). The mixture was treated with hydrazine hydrate (143 ml; 2.95 mol) at room temperature and was stirred for a further 26 h. The precipitate was filtered and the residue purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH₂Cl₂ (5 to 15% MeOH) to give Ce as a white solid (31.4 g).

Yield: 77%

¹H NMR spectrum (DMSO d₆): 1.12 (d, 3H); 1.25 (s, 6H); 1.42 (m, 4H); 1.61 (m, 4H), 2.31 (s, 6H); 2.63 (m, 2H); 2.72 (m, 1H); 4.15 (m, 2H); 4.57 (m, 2H); 7.02 (s, 1H); 7.06 (s, 2H); 8.9 (br s, 1H).

MS-ESI: 425 [M+H]⁺

A solution of Ce (1.5 g; 3.58 mmol) in THF (70 ml) was cooled to 0° C. under argon. DIEA (810 μl; 4.65 mmol) was added followed by a solution of DNOSCl (1.04 g; 3.9 mmol) in THF (20 ml). The mixture was allowed to warm to room temperature for 2 h and was treated with aq. HCl (1N). The mixture was extracted with CH₂Cl₂ and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 100% EtOAc) to give Cf as a cream foam (2.07 g).

Yield: 88%

¹H NMR spectrum (DMSO d₆): 1.10 (d, 3H); 1.23 (s, 6H); 1.41 (m, 4H); 1.58 (m, 4H); 2.29 (s, 6H); 2.83 (m, 1H); 3.19 (m, 2H); 4.13 (m, 2H); 4.55 (m, 2H); 6.95 (s, 2H); 6.98 (s, 1H); 8.12 (d, 1H); 8.49 (br s, 1H); 8.52 (q, 1H); 8.79 (d, 1H).

MS-ESI: 655 [M+H]⁺

A mixture of Cf (1.5 g; 2.3 mmol), the corresponding alcohol (575 mg; 3.45 mmol) and triphenylphosphine (3.67 g; 14 mmol) in THF (50 ml) at 0° C. under argon was treated with DTAD (2.12 g; 9.2 mmol). The mixture was allowed to warm to room temperature for 1 h when water was added. The mixture was extracted with CH₂Cl₂ and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/hexanes (0 to 50%) and then EtOAc/CH₂Cl₂ (0 to 100% EtOAc) to give CR17 as a beige solid (4.2 g).

This partially purified intermediate (containing some Ph₃PO) was used directly in the final step.

Example 4.1-4.54

The following examples were prepared using the same methodology as Example 4,

The table shows the R group relating to the above structure, the reaction conditions and characteristics of each example, corresponding to the description of the preparation of Example 4 given above:—

Example 4.1

CR1 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

100; 0.13 5 0.11; 1.3 53; 78% 530 [M + H]⁺ Chromato. - EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.12 (d, 3H); 1.25 (s, 6H); 1.41 (m, 4H); 1.60 (m, 4H); 2.28 (s, 6H); 2.6-2.9 (m, 7H); 4.14 (s, 2H); 4.57 (s, 2H); 7.03 (s, 3H); 7.12 (d, 2H); 8.39 (d, 2H); 11.8 (s br 1H).

Example 4.2

CR2 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

202; 0.25 3 0.21; 2.5 130; 91% 558 [M + H]⁺ Chromato. - EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14 (d, 3H); 1.25 (s, 6H); 1.35 (m, 2H); 1.42 (m, 4H); 1.53 (m, 2H); 1.61 (m, 4H); 2.29 (s, 6H); 2.5-2.95 (m, 7H); 4.15 (s, 2H); 4.57 (s, 2H); 7.03 (s, 1H); 7.05 (s, 2H); 7.17 (d, 2H); 8.42 (d, 2H) 11.8 (s br 1H).

Example 4.3

CR3 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

68; 0.09 3 0.08; 0.88 42; 87% 544 [M + H]⁺ Chromato. - EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆ - TFAd): 1.25 (m, 9H); 1.43 (m, 4H); 1.60 (m, 4H); 1.97 (m, 2H); 2.32 (s, 6H); 2.8-3.15 (m, 7H); 4.20 (s, 2H); 4.55 (s, 2H); 7.03 (s, 2H); 7.07 (s, 1H) 7.96 (d, 2H); 8.89 (d, 2H); 11.8 (s br 1H).

Example 4.4

CR4 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

514; 0.19 3 0.165; 2 75; 68% 557 [M + H]+ Chromato. - EtOAc ¹H NMR spectrum (DMSO d₆): 1.12 (d, 3H); 1.25 (s, 6H); 1.32 (m, 2H); 1.42 (m, 4H); 1.50; (m, 2H); 1.61 (m, 4H); 2.28 (s, 6H); 2.35-2.85 (m, 7H); 4.14 (s, 2H); 4.57 (s, 2H); 7.01 (s, 1H); 7.06 (s, 2H); 7.15 (m, 3H); 7.24 (m, 2H); 11.8 (s br 1H).

Example 4.5

CR5 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

1600; 0.5 30 0.58; 7 185; 63% 587 [M + H]+ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d6): 1.13 (d, 3H); 1.25 (s, 6H); 1.35 (m, 2H); 1.44 (m, 4H); 1.47; (m, 2H); 1.61 (m, 4H); 2.29 (s, 6H); 2.4-2.9 (m, 7H); 3.70 (s, 3H); 4.15 (s, 2H); 4.57 (s, 2H); 6.81 (d, 2H); 7.04 (m, 5H); 11.8 (s br 1H).

Example 4.6

CR6 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

230; 0.23 5 0.19; 2.3 103; 56% xxx [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (75 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH). ¹H NMR spectrum (DMSO d₆): 1.14 (d, 3H); 1.25 (s, 6H); 1.37 (m, 2H); 1.42 (m, 4H); 1.54 (m, 2H); 1.59 (m, 4H); 2.28 (s, 6H); 2.55-2.95 (m, 7H); 4.15 (s, 2H); 4.57 (s, 2H); 7.02 (s, 1H); 7.05 (s, 2H); 7.44 (d, 2H); 8.14 (d, 2H); 11.8 (s br 1H)..

Example 4.7

CR7 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

nd*; 0.23 5 0.19; 2.3 48; 37% 559 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.17 (d, 3H); 1.25 (s, 6H); 1.42 (m, 4H); 1.48 (m, 2H); 1.61 (m, 4H); 1.71 (m, 2H); 2.3 (s, 6H); 2.55-3.0 (m, 7H); 4.17 (s, 2H); 4.58 (s, 2H); 7.04 (m, 3H); 7.32 (t, 1H); 8.71 (d, 2H); 11.8 (s br 1H).

Example 4.8

CR8 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

nd*; 0.23 3 0.19; 2.3 71; 54% 559 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14 (d, 3H); 1.25 (s, 6H); 1.42 (m, 6H); 1.63 (m, 6H); 2.29 (s, 6H); 2.55-2.9 (m, 7H); 4.16 (s, 2H); 4.57 (s, 2H); 7.02 (s, 1H); 7.05 (s, 2H); 8.45 (d, 1H); 8.52 (m, 2H); 11.8 (s br 1H)..

Example 4.9

CR9 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

nd*; 0.38 10 0.31; 3.8 94; 45% 554 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d6): 1.12 (d, 3H); 1.24 (s, 6H); 1.41 (m, 4H); 1.60 (m, 4H); 2.29 (s, 6H); 2.6-2.9 (m, 7H); 4.15 (s, 2H); 4.56 (s, 2H); 7.02 (s, 3H); 7.31 (d, 2H); 7.68 (d, 2H); 11.8 (s br 1H).

Example 4.10

CR10 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

nd*; 0.23 3 0.19; 2.3 50; 38% 579 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 7% MeOH) ¹H NMR spectrum (DMSO d₆): 1.16 (d, 3H); 1.25 (s, 6H); 1.40 (m, 4H); 1.59 (m, 4H); 2.27 (s, 6H); 2.55-2.95 (m, 7H); 4.16 (m, 2H); 4.56 (s, 2H); 7.03 (s, 1H); 7.04 (s, 2H); 7.3 (d, 1H); 7.46 (m, 2H); 7.62 (s, 1H); 7.8 (m, 2H); 7.86 (d, 1H); 11.8 (s br 1H).

Example 4.11

R CR11 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.23 3 0.19; 2.3 88; 68% 559 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.61(m, 4H); 2.29(s, 6H); 2.6-2.95(m, 5H); 3.45(s, 2H); 4.16(s, 2H); 4.41(s, 2H); 4.56(s, 2H); 7.03(s, 1H); 7.06(s, 2H); 7.2-7.35(m, 6H); 11.8(s br 1H).

Example 4.12

R CR12 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.46 10 0.38; 4.6 152; 62% 529 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.60(m, 4H); 2.29(s, 6H); 2.45-2.95(m, 7H); 4.15(s, 2H); 4.57(s, 2H); 7.03(s, 1H); 7.04(s, 2H), 7.10(d, 2H); 7.16(t, 1H); 7.24(t, 2H); 11.8(s br 1H).

Example 4.13

R CR13 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.38 20 450; 7.6 154; 68% 597 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 7% MeOH) 1H NMR spectrum (DMSO d6): 1.12(d, 3H); 1.25(s, 6H); 1.41(m, 4H); 1.6(m, 4H); 2.27(s, 6H); 2.6-2.9(m, 7H); 4.14(m, 2H); 4.56(s, 2H); 7.02(s, 1H); 7.03(s, 2H); 7.45(m, 4H); 11.8(s br 1H).

Example 4.14

R CR14 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 105; 71% 589 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (50 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.13(d, 3H); 1.25(s, 6H); 1.41(m, 4H); 1.60(m, 4H); 2.29(s, 6H); 2.6-2.9(m, 7H), 3.68(s, 3H); 3.70(s, 3H); 4.15(s, 2H); 4.57(s, 2H); 6.60(q, 1H); 6.72(d, 1H); 6.79(d, 1H); 7.03(s, 1H); 7.05(s, 1H); 11.8(s br 1H).

Example 4.15

R CR15 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.25 5 0.295; 5 32; 22% 572 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.16(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.60(m, 4H); 2.30(s, 6H); 2.6-2.9(m, 7H); 2.83(s, 6H); 4.16(s, 2H); 4.57(s, 2H); 6.61(d, 2H0; 6.92(d, 2H); 7.04(s, 3H); 11.8(s br 1H).

Example 4.16

R CR16 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.46 10 0.380; 4.6 149; 59% 547 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.13(d, 3H); 1.25(s, 6H); 1.41(m, 4H); 1.60(m, 4H); 2.29(s, 6H); 2.55-2.95(m, 7H); 4.15(s, 2H); 4.57(s, 2H); 7.03(m, 5H); 7.12(m, 2H); 11.8(s br 1H).

Example 4.17

R CR18 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 61; 43% 565 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (50 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (CDCl₃): 1.21(d, 3H); 1.35(d, 6H); 1.44(m, 4H); 1.75(m, 4H); 2.33(s, 6H); 2.6-3.1(m, 7H); 4.26(m, 2H); 4.63(s, 2H); 6.61(m, 3H); 7.01(s, 3H); 9.1(s br, 1H).

Example 4.18

R CR19 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 53; 36% 585 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14(d, 3H); 1.25(s, 15H); 1.41(m, 4H); 1.6(m, 4H); 2.29(s, 6H); 2.55-2.95(m, 7H); 4.15(s, 2H); 4.56(s, 2H); 7.02(d, 2H); 7.03(s, 1H); 7.04(s, 2H); 7.25(d, 2H); 11.8(s br 1H).

Example 4.19

R CR20 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 40; 29% 557 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.18(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.6(m, 4H); 2.16(s, 3H); 2.20(s, 3H); 2.30(s, 6H); 2.5-2.95(m, 7H); 4.17(s, 2H); 4.56(s, 2H); 6.84(s, 1H); 6.88(d, 1H); 6.99(s, 1H); 7.05(s, 3H); 11.8(s br 1H).

Example 4.20

R CR21 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 49; 34% 581 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.13(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.61(m, 4H); 2.29(s, 6H); 2.55-2.9(m, 7H); 4.15(s, 2H); 4.57(s, 2H); 7.02(s, 1H); 7.04(s, 2H); 7.15(m, 1H); 7.27(m, 2H); 11.8(s br 1H).

Example 4.21

R CR22 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 64; 44% 581 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.13(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.6(m, 4H); 2.29(s, 6H); 2.55-2.95(m, 7H); 4.15(s, 2H); 4.56(s, 2H); 7.02(s, 1H); 7.04(s, 2H); 7.10(m, 1H); 7.26(m, 1H); 7.35(m, 1H); 11.8(s br 1H).

Example 4.22

R CR23 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 50; 34% 597 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.13(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.6(m, 4H); 2.28(s, 6H); 2.55-2.95(m, 7H); 4.16(m, 2H); 4.56(s, 2H); 7.03(s, 3H); 7.11(d, 1H); 7.41(s, 1H) 7.48(d, 1H); 11.8(s br 1H).

Example 4.23

CR24 mg; Propyl- Mass mmol CH₂Cl₂ amine mg; R Cf ml ml; mmol Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 40; 27% 597 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14(d, 3H); 1.25(s, 6H); 1.41(m, 4H); 1.61(m, 4H); 2.29(s, 6H); 2.55-2.95(m, 7H); 4.15(s, 2H); 4.57(s, 2H); 7.02(s, 1H); 7.05(s, 2H); 7.25(t, 1H); 7.4(d, 2H); 11.8(s br 1H).

Example 4.24

R CR25 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.23 5 540; 9.2 50; 37% 580 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.13(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.61(m, 4H); 2.31(s, 6H); 2.55-2.95(m, 3H); 3.1-3.75(m, 4H); 3.67(m, 2H); 4.15(s, 2H); 4.57(s, 2H); 4.62(m, 1H); 4.68(m, 1H); 4.76(s, 1H); 4.93(s, 1H); 7.03(s, 1H); 7.06(s, 1H); 11.8(s br 1H).

Example 4.25

R CR26 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.23 5 0.810; 13.2 68; 52% 566 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.13(d, 3H); 1.26(s, 6H); 1.42(m, 4H); 1.62(m, 4H); 2.03(m, 2H); 2.31(s, 6H); 2.33(m, 3H); 2.55-2.95(m, 6H); 4.14(s, 2H); 4.49(m, 2); 4.58(s, 2H); 4.71(s, 1H); 4.8(s, 1H); 7.03(s, 1H); 7.06(s, 2H); 11.8(s br 1H).

Example 4.26

CR27 mg; Propyl- Mass mmol CH₂Cl₂ amine mg; R Cf ml ml; mmol Yield MS-ESI

nd*; 0.26 5 0.27; 3.3 55; 38% 547 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.6(m, 4H); 2.29(s, 6H); 2.55-2.95(m, 7H); 4.15(s, 2H); 4.57(s, 2H); 6.97(m, 3H); 7.03(s, 3H); 7.27(m, 1H); 11.8(s br 1H).

Example 4.27

CR28 mg; Propyl- Mass mmol CH₂Cl₂ amine mg; R Cf ml ml; mmol Yield MS-ESI

nd*; 0.26 5 0.27; 3.3 40; 27% 563 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.6(m, 4H); 2.29(s, 6H); 2.55-2.95(m, 7H); 4.15(m, 2H); 4.57(s, 2H); 7.03(s, 3H); 7.09(m, 1H); 7.25(m, 3H); 11.8(s br 1H).

Example 4.28

CR29 mg; Propyl- Mass mmol CH₂Cl₂ amine mg; R Cf ml ml; mmol Yield MS-ESI

nd*; 0.26 5 0.27; 3.3 47; 32% 559 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.16(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.6(m, 4H); 2.3(s, 6H); 2.55-2.95(m, 7H); 3.71(s, 3H); 4.16(s, 2H); 4.56(s, 2H); 6.7(m, 3H); 7.04(s, 3H); 7.16(m, 1H); 11.8(s br 1H).

Example 4.29

CR30 mg Propyl- Mass mmol CH₂Cl₂ amine mg; R Cf ml mmol Yield MS-ESI

nd*; 0.26 5 0.27; 3.3 70; 49% 543 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14(d, 3H); 1.25(s, 6H); 1.42(m, 4H); 1.6(m, 4H); 2.24(s, 3H); 2.3(s, 6H); 2.55-2.95(m, 7H); 4.16(s, 2H); 4.57(s, 2H); 6.90(m, 2H); 6.98(d, 1H); 7.04(s, 3H); 7.12(t, 1H); 11.8(s br 1H).

Example 4.30

R CR31 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.26 5 0.27; 3.3 64; 43% 563 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14(d, 3H); 1.25(m, 6H); 1.42(m, 4H); 1.6(m, 4H); 2.29(s, 6H); 2.5-2.9(m, 7H); 4.16(s, 2H); 4.56(m, 2H); 7.03(s, 3H); 7.14(d, 2H); 7.29(d, 2H); 11.8(s br 1H).

Example 4.31

CR32 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

nd*; 0.26 5 0.27; 3.3 143; 100% 543 [M + H]⁺ Chromato.—MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14 (d, 3 H); 1.25 (m, 6 H); 1.42 (m, 4 H); 1.6 (m, 4 H); 2.24 (s, 3 H); 2.29 (s, 6 H); 2.5-2.95 (m, 7 H); 4.15 (s, 2 H); 4.56 (m, 2 H); 6.98 (d, 2 H); 7.04 (m, 5 H); 11.8 (s br 1 H).

Example 4.32

CR33 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

nd*; 0.26 5 0.27; 3.3 133; 90% 559 [M + H]⁺ Chromato.—MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.13 (d, 3 H); 1.25 (m, 6 H); 1.42 (m, 4 H); 1.6 (m, 4 H); 2.29 (s, 6 H); 2.5-2.95 (m, 7 H); 3.70 (s, 3 H); 4.15 (s, 2 H); 4.56 (m, 2 H); 6.79 (d, 2 H); 7.01; (d, 2 H); 7.04 (s, 3 H); 11.8 (s br 1 H).

Example 4.33

CR34 Propyl- mg; amine Mass mmol CH₂Cl₂ ml; mg; R Cf ml mmol Yield MS-ESI

nd*; 0.26 5 0.27; 3.3 51; 35% 547 [M + H]⁺ Chromato.—MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14 (d, 3 H); 1.25 (m, 6 H); 1.42 (m, 4 H); 1.6 (m, 4 H); 2.29 (s, 6 H); 2.5-2.95 (m, 7 H); 3.70 (s, 3 H); 4.16 (m, 2 H); 4.56 (s, 2 H); 7.04 (s, 3 H); 7.09 (m, 2 H); 7.21; (m, 2 H); 11.8 (s br 1 H).

Example 4.34

Example 4.34 was prepared by a different methodology (opening of epoxide by Ce): see below.

Example 4.35

CR36 mg; CH₂Cl₂ Propylamine ml; Mass mg; R mmol Cf ml mmol Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 78; 55% 565 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (50 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.13 (d, 3 H); 1.25 (s, 6 H); 1.42 (m, 4 H); 1.61 (m, 4 H); 2.29 (s, 6 H); 2.55-2.95 (m, 7 H); 4.14 (m, 2 H); 4.57 (s, 2 H); 6.94 (m, 1 H); 7.03 (s, 3 H); 7.15 (m, 1 H); 7.26 (m, 1H); 11.8 (s br 1 H).

Example 4.36

CR37 mg; CH₂Cl₂ Propylamine ml; Mass mg; R mmol Cf ml mmol Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 32; 22% 589 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (50 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14 (d, 3 H); 1.25 (s, 6 H); 1.41 (m, 4 H); 1.60 (m, 4 H); 2.29 (s, 6 H); 2.55-2.95 (m, 7 H); 3.68 (s, 6 H); 4.15 (m, 2 H); 4.57 (s, 2 H); 6.3 (m, 3 H); 7.03 (s, 1 H); 7.04 (s, 2 H); 11.8 (s br 1 H).

Example 4.37

CR38 mg; CH₂Cl₂ Propylamine ml; Mass mg; R mmol Cf ml mmol Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 102; 66% 619 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (50 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14 (d, 3 H); 1.25 (s, 6 H); 1.41 (m, 4 H); 1.60 (m, 4 H); 2.29 (s, 6 H); 2.55-2.95 (m, 7 H); 3.60 (s, 3 H); 3.69 (s, 6 H); 4.14 (s, 2 H); 4.56 (s, 2 H); 6.42 (s, 2 H); 7.02 (s, 1 H); 7.05 (s, 2 H); 11.8 (s br 1 H).

Example 4.38

CR39 mg; CH₂Cl₂ Propylamine ml; Mass mg; R mmol Cf ml mmol Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 91; 62% 589 [M + H]⁺ Chromato.—EtOAc/CH2Cl2 (50 to 100% EtOAc) and then MeOH/CH2Cl2 (0 to 10% MeOH) ¹H NMR spectrum (DMSO d6): 1.15 (d, 3 H); 1.25 (s, 6 H); 1.42 (m, 4 H); 1.61 (m, 4 H); 1.78 (m, 2 H); 2.29 (s, 6 H); 2.55-2.95 (m, 5 H); 3.68 (s, 3 H); 3.88 (t, 2 H); 4.15 (s, 2 H); 4.56 (s, 2 H); 6.80 (m, 4 H); 7.02 (s, 1 H); 7.06 (s, 2 H); 11.8 (s br 1 H).

Example 4.39

CR40 mg; CH₂Cl₂ Propylamine ml; Mass mg; R mmol Cf ml mmol Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 85; 61% 562 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (50 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH). ¹H NMR spectrum (DMSO d₆): 1.13 (d, 3 H); 1.25 (s, 6 H); 1.42 (m, 4 H); 1.61 (m, 4 H); 2.08 (s, 6 H); 2.30 (s, 6 H); 2.55-2.95 (m, 3 H); 3.35 (s, 2 H); 3.53 (s, 2 H); 4.14 (m, 2 H); 4.57 (s, 2 H); 6.01 (d, 1 H); 6.10 (d, 1 H); 7.03 (s, 1 H); 7.05 (s, 2 H), 11.8 (s br 1 H).

Example 4.40

CR41 mg; CH₂Cl₂ Propylamine ml; Mass mg; R mmol Cf ml mmol Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 40; 29% 544 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (50 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14 (d, 3 H); 1.25 (s, 6 H); 1.41 (m, 4 H); 1.61 (m, 4 H); 2.29 (s, 6 H); 2.55-2.95 (m, 5 H); 3.01; (m, 2 H); 4.14 (s, 2 H); 4.56 (s, 2 H); 5.37 (s, 1 H); 6.50 (m, 3 H); 7.04 (m, 5 H); 11.8 (s br 1 H).

Example 4.41

CR42 mg; CH₂Cl₂ Propylamine ml; Mass mg; R mmol Cf ml mmol Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 87; 64% 541 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (50 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.16 (d, 3 H); 1.20 (m, 6 H); 1.41 (m, 4 H); 1.61 (m, 4 H); 2.30 (s, 6 H); 2.55-2.95 (m, 3 H); 3.27 (m, 2); 4.13 (s, 2 H); 4.53 (s, 2 H); 6.23 (m, 1 H); 6.42 (d, 1 H); 7.04 (s, 1 H); 7.07 (s, 2 H); 7.21 (t, 1 H); 7.30 (t, 2 H); 7.35 (d, 2 H); 11.8 (s br 1 H).

Example 4.42

CR43 mg; CH₂Cl₂ Propylamine ml; Mass mg; R mmol Cf ml mmol Yield MS-ESI

nd*; 0.25 5 0.27; 4.5 98; 72% 545 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (50 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14 (d, 3H); 1.20 (m, 6H); 1.42 (m, 4H); 1.61 (m, 4H); 2.31 (s, 6H); 2.61 (m, 1H); 2.68 (m, 1H); 2.85 (m, 1H); 3.53 (s, 2H); 3.70 (s, 3H); 4.12 (m, 2H); 4.56 (s, 2H); 6.81 (d, 2H); 7.03 (s, 1H); 7.07 (s, 2H); 7.12 (d, 2H); 11.8 (s br 1H).

Example 4.43

CR44 mg; CH₂Cl₂ Propylamine Mass mg; MS- R mmol Cf ml ml; mmol Yield ESI

nd*; 0.25 5 0.27; 3.3 100; 63% 629 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (0 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.08 (d, 6H); 1.18 (d, 3H); 1.26 (s, 6H); 1.42 (m, 4H); 1.60 (m, 4H); 2.31 (s, 6H); 2.55-2.95 (m, 7H); 3.73 (m, 1H); 4.18 (m, 2H); 4.56 (s, 2H); 5.95 (s, 1H); 6.96 (d, 2H); 7.04 (s, 3H); 7.25 (d, 2H); 8.22 (s, 1H); 11.8 (s br 1H).

Example 4.44

Example C45 was prepared by a different methodology (reductive amination of Ce): see below.

Example 4.45

CR46 mg; CH₂Cl₂ Propylamine ml; Mass mg; R mmol Cf ml mmol Yield MS-ESI

108; 0.14 3 0.17; 2.0 71; 93% 544 [M + H]⁺ Chromato.—EtOAc and then MeOH/CH₂Cl₂ (0 to 15% MeOH) ¹H NMR spectrum (DMSO d₆): 1.14 (d, 3H); 1.25 (s, 6H); 1.42 (m, 4H); 1.61 (m, 4H); 2.3 (s, 6H); 2.55-2.95 (m, 7H); 4.14 (s, 2H); 4.57 (s, 2H); 4.83 (s, 2H); 6.44 (d, 2H); 6.74 (d, 2H); 7.04 (s, 1H); 7.05 (s, 2H); 11.8 (s br, 1H).

Example 4.46

CR47 mg; CH₂Cl₂ Propylamine ml; Mass mg; MS R mmol ml mmol Yield ESI

nd*; 0.14 5 0.15; 1.8 41; 45% 640 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (0 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.18 (d, 3H); 1.25 (m, 6H); 1.42 (m, 4H); 1.5-1.9 (m, 12H); 2.31 (s, 6H); 2.55-2.95 (m, 8H); 4.16 (m, 2H); 4.56 (s, 2H); 7.03 (m, 5H); 7.51 (d, 2H); 9.81; (s, 1H); 11.8 (s br, 1H).

Example 4.47

CR48 mg; CH₂Cl₂ Propylamine ml; Mass mg; MS- R mmol Cf ml mmol Yield ESI

nd*; 0.15 3 0.12; 1.5 135; 99% 700 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (0 to 100% EtOAc) ¹H NMR spectrum (DMSO d₆-TFAd): 1.28 (m, 9H); 1.43 (m, 4H); 1.62 (m, 4H); 2.33 (s, 6H); 2.8-3.25 (m, 7H); 3.51 (s, 6H); 4.23 (m, 2H); 4.57 (s, 2H); 7.05 (s, 2H); 7.08 (s, 1H); 7.31 (d, 2H); 7.47 (d, 2H); 11.8 (s br, 1H).

Example 4.48

CR49 mg; CH₂Cl₂ Propylamine ml; Mass mg; R mmol Cf ml mmol Yield MS-ESI

nd*; 0.25 3 0.15; 2.5 80; 60% 535 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (0 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.13 (d, 3H); 1.25 (s, 6H); 1.42 (m, 4H); 1.61 (m, 4H); 2.30 (s, 6H); 2.55-2.95 (m, 7H); 4.15 (m, 2H); 4.57 (s, 2H); 6.76 (d, 1H); 6.90 (dd, 1H); 7.02 (s, 1H); 7.05 (s, 2H); 7.27 (d, 1H); 11.76 (s br, 1H).

Example 4.49

CR50 mg; CH₂Cl₂ Propylamine ml; Mass mg; MS- R mmol Cf ml mmol Yield ESI

nd*; 0.6 5 0.355; 6 181; 49% 622 [M + H]⁺ Chromato.—MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.12 (d, 3H); 1.25 (s, 6H); 1.41 (m, 4H); 1.60 (m, 4H); 2.29 (s, 6H); 2.55-2.85 (m, 7H); 2.92 (s, 3H); 4.14 (s, 2H); 4.57 (s, 2H); 7.06 (m, 7H); 11.74 (s br, 1H).

Example 4.50

CR51 mg; CH₂Cl₂ Propylamine ml; Mass mg; MS- R mmol Cf ml mmol Yield ESI

nd*; 0.15 3 0.09; 1.5 63; 67% 630 [M + H]⁺ Chromato.—MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.16 (d, 3H); 1.25 (m, 12H); 1.42 (m, 4H); 1.60 (m, 4H); 2.30 (s, 6H); 2.55-2.95 (m, 7H); 4.16 (m, 2H); 4.5 (s, 2H); 4.87; (m, 1H); 7.0 (d, 2H); 7.04 (s, 3H); 7.34 (s, 2H); 9.44 (s, 1H); 11.8 (s br, 1H).

Example 4.51

CR52 mg; CH₂Cl₂ Propylamine ml; Mass mg; MS- R mmol Cf ml mmol Yield ESI

nd*; 0.11 2 0.065; 1.1 42; 57% 669 [M + H]⁺ Chromato.—MeOH/CH₂Cl₂ (0 to 15% MeOH) ¹H NMR spectrum (DMSO d₆): 1.16 (d, 3H); 1.25 (s, 6H); 1.25-1.8 (m, 18H); 2.31 (s, 6H); 2.55-2.95 (m, 7H); 3.43 (m, 1H); 4.16 (m, 2H); 4.56 (s, 2H); 6.04 (s, 1H); 6.96 (d, 2H); 7.04 (s, 3H); 7.25 (d, 2H); 8.25 (s, 1H); 11.86 (s br, 1H).

Example 4.52

CR53 mg; CH₂Cl₂ Propylamine Mass mg; R mmol Cf ml ml; mmol Yield MS-ESI

nd*; 0.4 5 0.24; 4 93; 44% 535 [M + H]⁺ Chromato.—EtOAc ¹H NMR spectrum (DMSO d₆): 1.13 (d, 3H); 1.25 (s, 6H); 1.1-1.7 (m, 21H); 2.3 (s, 6H); 2.35-2.85 (m, 5H); 4.15 (s, 2H); 4.57 (s, 2H); 7.03 (s, 1H); 7.06 (s, 2H) 11.8 (s br, 1H).

Example 4.53

Example 4.53 was prepared by a different methodology (alkylation of Ce): see below

Example 4.54

R CR55 mg; mmol Cf CH₂Cl₂ ml Propylamine ml; mmol Mass mg; Yield MS-ESI

nd*; 0.25 5 0.15; 2.5 64; 42% 610 [M + H]⁺ Chromato. - EtOAc and then MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆): 1.16(m, 3H); 1.25(s, 6H); 1.41(m, 4H); 1.59(m, 4H); 2.28(s, 6H); 2.55-3.0(m, 7H); 3.60(s, 3H); 4.16(s, 2H); 4.56(s, 2H); 6.6(d, 1H); 7.02(s, 3H); 7.42(m, 3H); 7.81(d, 1H); 11.8(s br, 1H). *nd = not determined, partially purified CR used idrectly from previous step.

Example 4.34 2-[3-(2, methyl-3-oxo-3-azabicyclo[2.2.1]heptan-7-ylpropoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-hydroxy-2-phenylethyl]-(2S)-propylamine

A solution of Ce (106 mg; 0.25 mmol) in acetonitrile (3 ml) was treated with styrene oxide and the mixture was heated at 60° C. overnight. The solvent was evaporated and the residue purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH₂Cl₂ hexanes (0 to 10% MeOH) to give Example 4.34 as a white foam (40 mg).

Yield: 30%.

¹H NMR spectrum (DMSO d₆): 1.15 (m, 3H); 1.26 (m, 6H); 1.42 (m, 4H); 1.61; (m, 4H); 2.29 (s, 6H); 2.55-2.95 (m, 5H); 4.16 (m, 2H); 4.57 (m, 3H); 7.06 (m, 3H); 7.26 (m, 5H); 11.6 (s br, 1H).

MS-ESI: 545 [M+H]⁺

Example 4.44 2-[3-(2,2-dimethyl-3-oxo-3-azabicyclo[2.2.1]heptan-7-ylpropoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-methyl-2-phenylethyl]-(2S)-propylamine

A solution of Ce (126 mg; 0.3 mmol) and 2-phenyl propionaldehyde (45 μl; 0.3 mmol) in methanol (6 ml) under argon was cooled to 0° C. Sodium cyanoborohydride (39 mg; 0.6 mmol) was added portionwise and the mixture was stirred for 3 h. The methanol was evaporated and the residue taken up in CH₂Cl₂. The organic phase was washed with sat. aq. NaHCO₃, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 100% EtOAc) and then MeOH/CH₂Cl₂ (0 to 10% MeOH) to give Example 4.44 as a white foam (88 mg).

Yield: 54%.

¹H NMR spectrum (DMSO d₆): 1.10 (m, 6H); 1.24 (s, 6H); 1.41 (m, 4H); 1.60 (m, 4H); 2.28 (m, 6H); 2.55-2.95 (m, 6H); 4.14 (s, 2H); 4.56 (s, 2H); 7.03 (s, 3H); 7.09 (t, 2H); 7.16 (d, 1H); 7.23 (t, 2H); 11.8 (s br 1H).

MS-ESI: 543 [M+H]⁺

Example 4.53 2-[3-(2,2-dimethyl-3-oxo-3-azabicyclo[2.2.1]heptan-7-ylpropoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[1H-1,2,3-benzotriazol-5-ylaminocarbonylmethyl]-(2S)-propylamine

To a solution of Ce (200 mg; 0.47 mmol) in DMA (1 ml) at 140° C. was added solid N-1H-1,2,3-benzotriazole-5-yl-2-chloroacetamide (98 mg; 0.47 mmol) over 5 min. The reaction mixture was heated at 140° C. for a further 5 min. The resulting orange solution was allowed to cool to room temperature and purified by flash chromatography on silica gel eluting with CH₂Cl/NH₃ in MeOH (0 to 5% NH₃ in MeOH) to give Example 4.53 (110 mg).

Yield: 37%

¹H NMR spectrum (CDCl₃): 1.20 (d, 3H); 1.22 (s, 6H); 1.40 (m, 4H); 1.70 (m, 4H); 2.31 (s, 6H); 2.77 (m, 1H); 2.99 (m, 2H); 3.34 (s, 2H), 4.28 (m, 2H); 4.57 (s, 2H); 5.37 (s, 1H); 6.95 (s, 2H); 7.02 (s, 1H); 7.17 (br d, 1H); 7.84 (br d, 1H); 8.26 (s, 1H); 9.50 (br s, 1H); 9.67 (s, 1H).

MS-ESI: 599 [M+]⁺

To a stirred solution of 5-aminobenzotriazole (1.00 g; 7.50 mmol) in THF (20 ml) at −10° C., were added triethylamine (0.987 g; 9.75 mmol) and chloroacetyl chloride (0.841 g; 7.50 mmol) dropwise over 5 min. The reaction mixture was allowed to warm to room temperature and stirred overnight.

The resulting precipitate was collected by filtration, washed with CH₂Cl₂ and dried to afford N-1H-1,2,3-benzotriazole-5-yl-2-chloroacetamide (1.32 g) as a beige solid.

Yield: 83.5%

¹H NMR spectrum (DMSO d₆): 4.33 (s, 2H); 7.42 (br d, 1H); 7.91 (br d, 1H); 8.35 (s, 1H).

MS-ESI: 211 [M+H]⁺

Intermediates for Examples 4.1-4.55, CR1-CR55 Respectively

Starting materials CR1-CR55 were prepared as follows, the table showing the reaction conditions and characteristics for each example, corresponding to the description of Example 4 given above:— CR1 R Cf mg; mmol Alcohol mg; mmol Ph₃P mg; mmol DEAD mg; mmol Mass mg MS-ESI

200; 0.3 44; 0.36 470; 1.8 170; 1.2 1.88 760 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc).

CR2 R Cf mg; mmol Alcohol mg; mmol Ph₃P mg; mmol DEAD mg; mmol Mass mg MS-ESI

200; 0.3 56; 0.37 470; 1.8 170; 1.2 202 788 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (50 to 100% EtOAc).

CR3 R Cf mg; mmol Alcohol mg; mmol Ph₃P mg; mmol DEAD mg; mmol Mass mg MS-ESI

80; 0.12 20; 0.15 192; 0.73 70; 0.49 68 774 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc).

CR4 R Cf mg; mmol Alcohol mg; mmol Ph₃P mg; mmol DEAD mg; mmol Mass mg MS-ESI

130; 0.2 36; 0.24 300; 1.13 100; 0.7 514 787 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 40% EtOAc)

CR5 R Cf mg; mmol Alcohol mg; mmol Ph₃P mg; mmol DTAD mg; mmol Mass mg MS-ESI

327; 0.5 100; 0.6 786; 3 460; 2 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 50% EtOAc).

CR6 R Cf mg; mmol Alcohol mg; mmol Ph₃P mg; mmol DEAD mg; mmol Mass mg MS-ESI

150; 0.23 53; 0.27 361; 1.38 0.145; 0.92 230 832 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc).

CR7 R Cf mg; mmol Alcohol mg; mmol Ph₃P mg; mmol DEAD mg; mmol Mass mg MS-ESI

150; 0.23 42; 0.27 361; 1.38 0.145; 0.92 nd* 789 [M + H]⁺ Chromato. - EtOAc

CR8 R Cf mg; mmol Alcohol mg; mmol Ph₃P mg; mmol DEAD mg; mmol Mass mg MS-ESI

150; 0.23 42; 0.27 360; 138 0.15; 90 nd* 789 [M + H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc)

CR9 R Cf mg; mmol Alcohol mg; mmol Ph₃P mg; mmol DEAD mg; mmol Mass mg MS-ESI

nd*; 0.38 81; 0.55 724; 2.76 0.245; 1.55 94; 45% nd* Chromato. - EtOAc

CR10 Alco- Cf hol Ph₃P DTAD mg; mg; mg; mg; Mass MS- R mmol mmol mmol mmol mg ESI

150; 0.23 47; 0.27 361; 1.38 212; 0.93 nd* 809 [M +H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 70% EtOAc).

CR11 Alco- Cf hol Ph₃P DTAD mg; mg; mg; mg; Mass MS- R mmol mmol mmol mmol mg ESI

150; 0.23 42; 0.27 361; 1.38 212; 0.93 nd* 789 [M +H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 70% EtOAc).

CR12 Alco- Cf hol Ph₃P DTAD mg; mg; mg; mg; Mass MS- R mmol mmol mmol mmol mg ESI

300; 0.46 73; 0.6 723; 2.76 423; 1.84 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 30% EtOAc).

CR13 Alco- Cf hol Ph₃P DTAD mg; mg; mg; mg; Mass MS- R mmol mmol mmol mmol mg ESI

250; 0.38 95; 0.5 600; 2.28 350; 1.52 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 40% EtOAc).

CR14 Alco- Cf hol Ph₃P DTAD mg; mg; mg; mg; Mass MS- R mmol mmol mmol mmol mg ESI

164; 0.25 55; 0.3 362; 1.38 212; 0.92 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 70% EtOAc)

CR15 Alco- Cf hol Ph₃P DTAD mg; mg; mg; mg; Mass MS- R mmol mmol mmol mmol mg ESI

164; 0.25 49; 0.3 362; 1.38 212; 0.92 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 100% EtOAc)

CR16 Alco- Cf hol Ph₃P DTAD mg; mg; mg; mg; Mass MS- R mmol mmol mmol mmol mg ESI

300; 0.46 84; 0.6 723; 2.76 423; 1.84 nd* 777 [M +H]⁺ Chromato. - EtOAc/CH₂Cl₂ (0 to 20 EtOAc).

CR18 Alco- Cf hol Ph₃P DTAD mg; mg; mg; mg; Mass MS- Cgx mmol mmol mmol mmol mg ESI

150; 0.23 50; 0.3 367; 1.4 212; 0.92 40 nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc)

CR19 Alco- Cf hol Ph₃P DTAD mg; mg; mg; mg; Mass MS- R mmol mmol mmol mmol mg ESI

163; 0.25 57; 0.32 393; 1.5 230; 1.0 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc)

CR20 Alco- Cf hol Ph₃P DTAD mg; mg; mg; mg; Mass MS- R mmol mmol mmol mmol mg ESI

163; 0.25 48; 0.32 393; 1.5 230; 1.0 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc)

CR21 Cf mg; Alcohol Ph₃P DTAD Mass MS- R mmol mg; mmol mg; mmol mg; mmol mg ESI

163; 0.25 56; 0.32 393; 1.5 230; 1.0 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc)

CR22 Cf mg; Alcohol Ph₃P DTAD Mass MS- R mmol mg; mmol mg; mmol mg; mmol mg ESI

163; 0.25 56; 0.32 393; 1.5 230; 1.0 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc)

CR23 Cf mg; Alcohol Ph₃P DTAD Mass MS- R mmol mg; mmol mg; mmol mg; mmol mg ESI

163; 0.25 61; 0.32 393; 1.5 230; 1.0 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc)

CR24 Cf mg; Alcohol Ph₃P DTAD Mass MS- R mmol mg; mmol mg; mmol mg; mmol mg ESI

163; 0.25 61; 0.32 393; 1.5 230; 1.0 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc) CR25

The intermediate CR25 was prepared as follows:—

A solution of Cf (150 mg; 0.23 mmol) in DMF (3 ml) was cooled to 0° C. and treated with potassium t-butoxide (40 mg). The bromomethyl amide (82 mg; 0.35 mmol) was added and the mixture allowed to warm to room temperature for 1 h. The mixture was treated with sat. aq. NaHCO₃ and extracted with CH₂Cl₂ The organic phase was washed with water, brine and dried over MgSO₄. The crude product was used directly in the final step. CR26 Cf mg; Alcohol Ph₃P DTAD Mass MS- R mmol mg; mmol mg; mmol mg; mmol mg ESI

150; 0.23 48; 0.3 367; 1.4 212; 0.92 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc).

CR27 Cf mg; Alcohol Ph₃P DTAD Mass MS- R mmol mg; mmol mg; mmol mg; mmol mg ESI

173; 0.26 45; 0.32 415; 1.58 243; 1.06 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc).

CR28 Cf mg; Alcohol Ph₃P DTAD Mass MS- R mmol mg; mmol mg; mmol mg; mmol mg ESI

173; 0.26 50; 0.32 415; 1.58 243; 1.06 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc).

CR29 Cf mg; Alcohol Ph₃P DTAD Mass MS- R mmol mg; mmol mg; mmol mg; mmol mg ESI

173; 0.26 49; 0.32 415; 1.58 243; 1.06 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc).

CR30 Cf mg; Alcohol Ph₃P DTAD Mass MS- R mmol mg; mmol mg; mmol mg; mmol mg ESI

173; 0.26 44; 0.32 415; 1.58 243; 1.06 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc).

CR31 Cf mg; Alcohol Ph₃P DTAD Mass MS- R mmol mg; mmol mg; mmol mg; mmol mg ESI

173; 0.26 50; 0.32 415; 1.58 243; 1.06 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20% EtOAc).

CR32 Cf Alcohol Ph₃P DTAD Mass MS- R mg; mmol mg; mmol mg; mmol mg; mmol mg ESI

173; 0.26 44; 0.32 415; 1.58 243; 1.06 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20 EtOAc).

CR33 Cf Alcohol Ph₃P DTAD Mass MS- R mg; mmol mg; mmol mg; mmol mg; mmol mg ESI

173; 0.26 44; 0.32 415; 1.58 243; 1.06 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20 EtOAc).

CR34 Cf Alcohol Ph₃P DTAD Mass MS- R mg; mmol mg; mmol mg; mmol mg; mmol mg ESI

173; 0.26 45; 0.32 415; 1.58 243; 1.06 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (0 to 20 EtOAc).

CR36 Cf Alcohol Ph₃P DTAD Mass MS- R mg; mmol mg; mmol mg; mmol mg; mmol mg ESI

164; 0.25 52; 0.33 393; 1.5 230; 1 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (10 to 50 EtOAc).

CR37 Cf Alcohol Ph₃P DTAD Mass MS- R mg; mmol mg; mmol mg; mmol mg; mmol mg ESI

164; 0.25 60; 0.33 393; 1.5 230; 1 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (10 to 50 EtOAc).

CR38 Cf Alcohol Ph₃P DTAD Mass MS- R mg; mmol mg; mmol mg; mmol mg; mmol mg ESI

164; 0.25 70; 0.33 393; 1.5 230; 1 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (10 to 50 EtOAc).

CR39 Cf Alcohol Ph₃P DTAD Mass MS- R mg; mmol mg; mmol mg; mmol mg; mmol mg ESI

164; 0.25 60; 0.33 393; 1.5 230; 1 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (10 to 50 EtOAc).

CR40 Cf Alcohol Ph₃P DTAD Mass MS- R mg; mmol mg; mmol mg; mmol mg; mmol mg ESI

164; 0.25 63; 0.33 393; 1.5 230; 1 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (10 to 50 EtOAc).

CR41 Cf Alcohol Ph₃P DTAD Mass MS- R mg; mmol mg; mmol mg; mmol mg; mmol mg ESI

164; 0.25 45; 0.33 393; 1.5 230; 1 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (10 to 50 EtOAc).

CR42 Cf Alcohol Ph₃P DTAD Mass MS- R mg; mmol mg; mmol mg; mmol mg; mmol mg ESI

164; 0.25 44; 0.33 393; 1.5 230; 1 nd* nd* Chromato. - EtOAc/CH₂Cl₂ (10 to 50 EtOAc).

CR43 Cf mg; Alcohol mg; Ph₃P mg; DTAD mg; Mass MS- R mmol mmol mmol mmol mg ESI

164; 0.25 46; 0.33 393; 1.5 230; 1 nd* nd* Chromato.—EtOAc/CH₂Cl₂ (10 to 50 EtOAc).

CR44 Cf mg; Alcohol mg; Ph₃P mg; DTAD mg; Mass MS- R mmol mmol mmol mmol mg ESI

164; 0.25 75; 0.33 393; 1.5 230; 1 nd* 859 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (0 to 100% EtOAc)

CR45 Cf mg; Alcohol mg; Ph₃P mg; DTAD mg; Mass MS- R mmol mmol mmol mmol mg ESI

410; 0.62 130; 0.94 975; 3.72 570; 2.48 458 (95%) 774 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (0 to 100% EtOAc) ¹H NMR spectrum (DMSO d₆): 1.16 (d, 3H); 1.28 (s, 6H); 1.42 (m, 4H); 1.60 (m, 4H); 2.28 (s, 6H); 2.40 (m, 2H); 3.06 (m, 1H); 3.18 (m, 2H); 3.45-3.75 (m, 2H); 4.17 (dd, 2H); 4.56 (s, 2H); 4.86 (s, 2H); 6.37 (d, 2H); 6.61 (d, 2H); 7.01 (s, 3H); 8.08 (d, 1H); 8.43 (dd, 1H); 8.86 (d, 1H); 11.8 (s br, 1H).

solution of CR46 (108 mg; 0.14 mmol) in CH₂Cl₂ (2 ml) was cooled to 0° C. and treated with DIEA (27 μl; 0.154 mmol). A solution of the acid chloride (14 μl; 0.11 mmol) in CH₂Cl₂ (1 ml) was added and the mixture allowed to warm to room temperature. The crude mixture was deprotected as described for C47 above. CR48 This intermediate was prepared using a method analogous to the preparation of CR47. Cg46 mg; DIEA μl; Acid chloride Mass MS- R mmol mmol μl; mmol CH₂Cl₂ mg ESI

120; 0.15 29; 0.16 30; 0.36 3 nd* nd* Chromato.—EtOAc

CR49 Cf mg; Alcohol mg; Ph₃P mg; DTAD mg; Mass MS- R mmol mmol mmol mmol mg ESI

164; 0.25 50; 0.37 393; 1.5 230; 1 nd* nd* Chromato.—EtOAc/CH₂Cl₂ (0 to 50% EtOAc)

CR50 This intermediate was prepared using a method analogous to the preparation of CR47. CR46 mg; DIBA μl; Acid chloride Mass MS- R mmol mmol μl; mmol CH₂Cl₂ mg ESI

630; 0.6 315; 1.8 95; 1.2 50 nd* nd* Chromato.—EtOAc/CH₂Cl₂ (0 to 100% EtOAc)

CR51 This intermediate was prepared using a method analogous to the preparation of CR47. CR46 mg; DIEA μl Acid chloride Mass MS- R mmol mmol μl; mmol CH₂Cl₂ mg ESI

120; 0.15 100; 0.6 300 1M; 0.15 3 nd* 860 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (0 to 50% EtOAc)

CR52 This intermediate was prepared using a method analogous to the preparation of CR47. CR46 Acid mg; DIEA μl; chloride** μl; Mass MS- R mmol mmol mmol CH₂Cl₂ mg ESI

88; 0.11 100; 0.6 50; 0.4 10 nd* nd* Chromato.—EtOAc/CH₂Cl₂ (0 to 50% EtOAc) **Cyclohexyl isocyanate was used in place of the correspondmg acid chloride.

CR53 Cf mg; Alcohol mg; Ph₃P mg; DTAD mg; Mass MS- R mmol mmol mmol mmol mg ESI

262; 0.4 102; 0.8 629; 2.4 368; 1.6 nd* nd* Chromato.—EtOAc/CH₂Cl₂ (0 to 20% EtOAc)

CR55 Cf mg; Alcohol mg; Ph₃P mg; DTAD mg; Mass MS- R mmol mmol mmol mmol mg ESI

164; 0.25 70; 0.34 393; 1.5 230; 1 nd* 840 [M + H]⁺ Chromato.—EtOAc/CH₂Cl₂ (0 to 20% EtOAc) *nd = not determined, partially purified Cgx used directly for final step.

Example 5 3-[2,2-dimethyl-3-oxo-3-(pyrrolidin-1-yl)propoxy]-4-[4-(2-pyrrolidin-1-yl-2-oxo-ethyl)piperzin-1-ylethyl]-5-(3,5-dimethylphenyl)-1H-pyrazole

solution of DR1 (350 mg; 0.53 mmol) in pyrrolidine (2 ml) was heated at 45° C. overnight. The pyrrolidine was evaporated and the residue purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH₂Cl₂ (0 to 7% MeOH) to give Example 5 as a colourless foam (288 mg).

Yield: 97%

¹H NMR spectrum (CDCl₃): 1.38 (s, 6H); 1.78 (m, 4H); 1.84 (m, 2H); 1.94 (m, 2H); 2.35 (s, 6H); 2.5-2.7 (m, 12H); 3.10 (s, 2H); 3.47 (t, 4H); 3.58 (m, 4H); 4.32 (s, 2H); 7.03 (s, 1H); 7.27 (s, 2H); 8.8 (s br, 1H).

MS-ESI: 565 [M+H]⁺

The starting material DR1 was prepared as follows:—

A solution of Ab5 (242 mg; 0.5 mmol) and 4-(4-aminobutyl)-pyridine (125 mg; 0.65 mmol) in DCE (5 ml) was treated with NaBH(OAc)₃ (425 mg; 2.0 mmol). The mixture was stirred for 20 h and evaporated. The residue was treated with aq. K₂CO₃ (10%) and the mixture extracted with EtOAc. The organic phase was washed with water, brine and dried over MgSO₄. The solution was evaporated to give pure DR1 as an white solid (350 mg).

Yield: 100%

¹H NMR spectrum (CDCl₃): 1.20 (s, 9H); 1.36 (s, 6H); 1.74 (s, 4H); 1.84 (m, 2H); 1.92 (m, 2H); 2.31 (s, 6H); 2.4-2.6 (m, 12H); 3.07 (s, 2H); 3.46 (t, 4H); 3.57 (m, 4H); 4.45 (s, 2H); 6.81 (s, 2H); 6.98 (s, 1H).

MS-ESI: 665 [M+H]⁺

Examples 5.1-5.2

The following Example 5.1 was prepared in a similar manner to Example 5 and Example 5.2 was prepared in a manner similar to Example 2.

the table shows the NRR′ group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 5 given above:— —NRR′ DR2 mg; mmol Pyrrolidine ml; mmol Prod. Form Mass mg; Yield MS-ESI

85; 0.14 2; 2.86 White glass 68; 96% 516 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (7 to 10% MeOH) ¹H NMR spectrum (CDCl₃): 1.39(s, 6H); 1.70(s, 4H); 1.83(m, 2H); 2.35(s, 6H); 2.5-2.9(m, 7H); 3.0(m, 1H); 3.3(m, 1H); 3.58(m, 4H); 4.34(dd, 2H); 7.03(s, 1H); 7.04(s, 2H); 7.17(d, 2H); 8.48(d, 2H); 8.9(s br 1H).

Example 5.2

—NRR′ DR3 mg; mmol CH₂Cl₂ Prod. Form Mass mg; Yield MS-ESI

194; 0.3 2 White solid 86; 52% 551 [M + H]⁺ Chromato. - LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (0 to 100% H₂O) ¹H NMR spectrum (CDCl₃): 1.36(s, 6H); 1.74(m, 4H); 1.83(m, 4H); 2.32(s, 6H); 2.4-2.7(m, 20H); 3.56(m, 4H); 4.30(s, 2H); 7.01(s, 1H); 7.02(s, 2H); 8.8(s br 1H). Intermediates for Examples 5.1-5.2, DR2-DR3 Respectively

Starting materials DR2-3 were prepared as follows, the table showing the reaction conditions and characteristics for each example, corresponding to the description of DR1 given above:—

DR2 —NRR′ Ab5 mg; mmol Amine mg; mmol NaBH(OAc)₃ mg; mmol Mass mg; Yield MS-ESI

150; 0.31 60; 0.39 200; 0.93 117; 61% 616 [M + H]⁺ Chromato. - EtOAc then MeOH/CH₂Cl₂ (5% MeOH) ¹H NMR spectrum (CDCl₃): 1.20(s, 9H); 1.37(s, 6H); 1.70(s, 4H); 1.90(m, 2H); 2.30(s, 6H); 2.4-2.7(m, 7H); 2.9(m, 1H); 3.3(m, 1H); 3.56(m, 4H); 4.47(dd, 2H); 6.80(s, 2H); 6.99(s, 1H); 7.15(d, 2H); 8.48(d, 2H).

DR3 —NRR′ Ab5 mg; mmol Amine mg; mmol NaBH₄ mg; mmol Mass mg; Yield MS-ESI

265; 0.55 110; 0.6 38; 0.6 + AcOH 35 μM 194; 54% 651 [M + H]⁺ Chromato. - Ammonia in MeOH(7N)/CH₂Cl₂ (0 to 10% ammonia in MeOH).

Example 6 3-[2,2-dimethyl-3-oxo-3-(azabicyclo[2.2.1]heptan-7-yl)propoxy]-4-[4-(2-pyrrolidin-1-yl-2-oxo-ethyl)piperzin-1-ylethyl]-5-(3,5-dimethylphenyl)-1H-pyrazole

A solution of ER1 (160 mg; 0.23 mmol) in pyrrolidine (1 ml) was heated at 45° C. overnight. The pyrrolidine was evaporated and the residue purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH₂Cl₂ (5 to 10% MeOH) to give Example 6 as a white solid (141 mg).

Yield: 100%

¹H NMR spectrum (CDCl₃): 1.36 (s, 6H); 1.46 (m, 4H); 1.77 (m, 4H); 1.83 (m, 2H); 1.93 (m, 2H); 2.35 (s, 6H); 2.45-2.65 (m, 12H); 3.11 (s, 2H); 3.47 (m, 4H); 4.28 (s, 2H); 4.65 (s, 2H); 7.03 (s, 2H); 7.26 (s, 1H); 8.8 (s br, 1H).

MS-ESI: 591 [M+H]⁺

Starting material ER1 was prepared as follows:—

DMAP (100 mg; cat.) was added to a solution of Bb (4.0 g; 9.72 mmol) in a mixture of acetonitrile (175 ml) and CH₂Cl₂ (40 ml). The mixture was cooled to −10° C. and a solution of (BOC)₂O (2.54 g; 11.66 mmol) in CH₂Cl₂ (50 ml) added dropwise during 1.5 h. The mixture was stirred for a further 2.5 h at −10° C. to −5° C. Water was added and the mixture stirred overnight at room temperature. The mixture was extracted with CH₂Cl₂ and the organic phase washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (20 to 80% EtOAc) to give the alcohol Ea as colourless crystals (2.4 g).

Yield: 48%

¹H NMR spectrum (CDCl₃): 1.20 (s, 9H); 1.34 (s, 6H); 1.45 (m, 4H); 1.77 (m, 4H); 2.32 (s, 6H); 2.42 (t, 2H); 3.63 (m, 2H); 4.42 (s, 2H); 4.65 (s, 2H); 6.83 (s, 2H); 7.00 (s, 1H)

MS-ESI: 512 [M+H]⁺

A solution of Ea (3.7 g; 7.23 mmol) and CBr₄ (3.12 g; 9.4 mmol) in CH₂Cl₂ (150 ml) was cooled to 0° C. under argon. Solid PPh₃ (2.84 g; 10.85 mmol) was added portionwise and the mixture allowed to warm to room temperature overnight. The mixture was directly purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 30% EtOAc) to give the bromide Eb as colourless crystals (3.01 g).

Yield: 73%

¹H NMR spectrum (DMSO d₆): 1.51 (s, 9H); 1.27 (s, 6H); 1.45 (m, 4H); 1.63 (m, 4H); 2.30 (s, 6H); 2.63 (t, 2H); 3.51 (t, 2H); 4.27 (s, 2H); 4.59 (s, 2H); 6.93 (s, 2H); 7.08 (s, 1H).

MS-ESI: 575 [M+H]⁺

A mixture of Eb (150 mg; 0.26 mmol) and 1-(pyrrolidinocarbonylmethyl)piperazine (108 mg; 0.548 mmol) in acetonitrile (5 ml) under argon was heated at 80° C. for 16 h. The solvent was evaporated and the residue was purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH₂Cl₂ (0 to 7% MeOH) to give ER1 as a beige powder (161 mg).

Yield: 89%

¹H NMR spectrum (CDCl₃): 1.20 (s, 9H); 1.34 (s, 6H); 1.46 (m, 4H); 1.77 (m, 4H); 1.85 (m, 2H); 1.94 (m, 2H); 2.32 (s, 6H); 2.35-2.6 (m, 12H); 3.01 (s, 2H); 3.46 (m, 4H); 4.42 (s, 2H); 4.65 (s, 2H); 6.82 (s, 2H); 7.00 (s, 1H).

MS-ESI: 691 [M+H]⁺

Examples 6.1-6.10

The following examples were prepared in a similar manner to Example 6,

the table shows the NRR′ group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 6 given above. The final two steps were carried out without purification or characterisation of the intermediates ER:—

Example 6.1

—NRR′ Eb mg; mmol Piperazine mg; mmol Pyrrolidine ml Mass mg; Yield MS-ESI

172; 0.3 116; 0.66 4 146; 85% 570 [M + H]⁺ Chromato. - Prep. LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H₂O) ¹H NMR spectrum (DMSO d₆): 1.24(s, 6H); 1.41(m, 4H); 1.61(m, 4H); 2.30(s, 6H); 2.3-2.6(m, 12H); 3.43(s, 2H); 4.14(s, 2H); 4.56(s, 2H); 7.01(s, 1H); 7.10(s, 2H); 7.3(m, 5H); 11.7(s br 1H).

Example 6.2

—NRR′ Eb mg; mmol Piperazine mg; mmol Pyrrolidine ml Mass mg; Yield MS-ESI

115; 0.2 94; 0.44 3 105; 87% 607 [M + H]⁺ Chromato. - Prep. LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (80% H₂O) ¹H NMR spectrum (DMSO d₆): 1.25(s, 6H); 1.42(m, 4H); 1.61(m, 4H); 2.31(s, 6H); 2.3-2.6(m, 12H); 3.10(s, 2H); 3.35-3.6(m, 8H); 4.15(s, 2H); 4.57(s, 2H); 7.02(s, 1H); 7.10(s, 2H); 11.7(s br 1H).

Example 6.3

—NRR′ Eb mg; mmol Piperazine mg; mmol Pyrrolidine ml Mass mg; Yield MS-ESI

115; 0.2 103; 0.44 3 96; 77% 627 [M + H]⁺ Chromato. - Prep. LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (80% H₂O) ¹H NMR spectrum (DMSO d₆): 1.25(s, 6H); 1.42(m, 4H); 1.61(m, 4H); 2.30(s, 6H); 2.3-2.6(m, 12H); 2.85(s br, 2H); 3.15(s br, 3H); 4.14(s, 2H); 4.57(s, 2H); 7.01(s, 1H); 7.09(s, 2H); 7.32(m, 3H); 7.41(m, 2H); 11.7(s br 1H).

Example 6.4

—NRR′ Eb mg; mmol Piperazine mg; mmol Pyrrolidine ml Mass mg; Yield MS-ESI

115; 0.2 84; 0.44 3 27; 25% 584 [M + H]⁺ Chromato. - Prep. LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H₂O) ¹H NMR spectrum (DMSO d₆): 1.25(s, 6H); 1.42(m, 4H); 1.62(m, 4H); 2.31(s, 6H); 2.3-2.6(m, 14H); 2.70(t, 2H); 4.15(s, 2H); 4.56(s, 2H); 7.02(s, 1H); 7.11(s, 2H); 7.17(t, 1H) 7.21(d, 2H); 7.26(t, 2H); 11.7(s br 1H).

Example 6.5

—NRR′ Eb mg; mmol Piperazine mg; mmol Pyrrolidine Mass mg; Yield MS-ESI

115; 0.2 78; 0.44 3 98; 86% 571 [M + H]⁺ Chromato. - Prep. LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (80% H₂O) ¹H NMR spectrum (DMSO d₆): 1.25(s, 6H); 1.41(m, 4H); 1.61(m, 4H); 2.30(s, 6H); 2.3-2.6(m, 12H); 3.48(s, 2H); 4.14(s, 2H); 4.57(s, 2H); 7.01(s, 1H); 7.10(s, 2H); 7.30(d, 2H); 8.49(dd, 2H); 11.7(s br 1H).

Example 6.6

—NRR′ Eb mg; mmol Piperazine mg; mmol Pyrrolidine ml Mass mg; Yield MS-ESI

115; 0.2 90; 0.44 3 19; 16% 598 [M + H]⁺ Chromato. - Prep. LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H₂O) ¹H NMR spectrum (DMSO d₆): 1.25(s, 6H); 1.42(m, 4H); 1.62(m, 4H); 1.69(m, 2H), 2.23(t, 2H); 2.30(s, 6H); 2.3-2.7(m, 14H); 4.14(s, 2H); 4.57(s, 2H); 7.01(s, 1H); 7.10(s, 2H); 7.17(m, 3H); 7.27(t, 2H); 11.7(s br 1H).

Example 6.7

Eb mg; Piperazine Pyrrolidine Mass mg; —NRR′ mmol mg; mmol ml Yield MS-ESI

115; 0.2 96; 0.44 3 108; 88% 612 [M + H]⁺ Chromato. - Prep. LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H₂O) ¹H NMR spectrum (DMSO d₆): 1.25 (s, 6H); 1.42 (m, 6H); 1.54 (m, 2H); 1.62 (m, 4H); 2.23 (t, 2H); 2.30 (s, 6H); 2.3-2.6 (m, 14H); 4.14 (s, 2H); 4.57 (s, 2H); 7.01 (s, 1H); 7.10 (s, 2H); 7.17 (m, 3H); 7.27 (t, 2H); 11.7 (s br 1H).

Example 6.8

Eb mg; Piperazine Pyrrolidine Mass mg; —NRR′ mmol mg; mmol ml Yield MS-ESI

115; 0.2 75; 0.44 3 91; 81% 563 [M + H]⁺ Chromato. - Prep. LC/MS H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (80% H₂O) ¹H NMR spectrum (DMSO d₆): 0.99 (m, 1H); 1.15 (m, 3H); 1.27 (s, 6H); 1.45 (m, 4H); 1.55-1.65 (m, 8H); 1.85 (t, 2H); 2.32 (s, 6H); 2.3-2.6 (m, 6H); 2.88 (d 2H); 3.25 (t, 2H); 3.86 (m, 2H); 4.16 (s, 2H); 4.59 (s, 2H); 7.03 (s, 1H); 7.12 (s, 2H); 11.86 (s br 1H).

Eb mg; Piperazine Pyrrolidine Mass mg; —NRR′ mmol mg; mmol ml Yield MS-ESI

230; 0.4 223; 0.84 10 234; 94% 623 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (CDCl₃) + CD₃OD): 1.26 (m, 6H); 1.37 (m, 4H); 1.60 (m, 4H); 1.71 (m, 1H); 1.97 (m, 2H); 2.1 (m, H1); 2.27 (s, 6H); 2.8-3.0 (m, 4H); 3.15 (m, 2H); 3.31 m, 1H); 3.61 (m, 2H); 4.14 (dd, 2H); 4.47 (s, 2H); 6.96 (s, 3H); 7.36 (d, 2H); 7.52 (d, 2H); 8.9 (s br, 1H).

Example 6.10

Eb mg; Piperazine Pyrrolidine Mass mg; —NRR′ mmol mg; mmol ml Yield MS-ESI

230; 0.4 113; 0.84 10 166; 79% 529 [M + H]⁺ Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (CDCl₃): 1.36 (s, 6H); 1.43 (m, 4H); 1.75 (m, 4H); 2.33 (s, 6H); 2.39 (s, 3H); 2.6-2.8 (m, 8H); 4.29 (s, 2H); 4.64 (s, 2H); 7.02 (s, 1H); 7.05 (s, 2H); 7.17 (m, 3H); 7.26 (m, 2H); 8.9 (s br 1H).

Example 7 3-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.2]oct-2-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(3-methoxyphenyl)ethyl]-(2S)-propylamine

A mixture of FR (167 mg; 0.25 mmol), 3-(2-hydroxyethyl)-methoxybenzene (50 mg; 0.325 mmol) and triphenylphosphine (393 mg; 1.5 mmol) in THF (5 ml) at 0° C. under argon was treated with DTAD (230 mgl; 1.0 mmol). The mixture was allowed to warm to room temperature for 1 h when water was added. The mixture was extracted with CH₂Cl₂ and the organic phase was washed with water, brine and dried over MgSO₄. The residue was taken up directly in CH₂Cl₂ (3 ml) and treated dropwise with n-propylamine (150 μl; 2.5 mmol). The mixture was stirred at room temperature for 1 h and then purified directly by flash chromatography eluting with increasingly polar mixtures of CH₂Cl₂ and then MeOH/CH₂Cl₂ (0 to 10% MeOH) to give Example 7 as a white foam (100 mg).

Yield: 70%

¹H NMR spectrum (DMSO d₆): 1.15 (d, 3H); 1.27 (s, 6H); 1.54 (m, 4H); 1.67 (m, 4H); 1.85 (s, 1H); 2.3 (s, 6H); 2.55-2.95 (m, 7H); 3.24 (m, 2H); 3.7 (s, 3H); 4.16 (m, 3H); 6.7 (m, 3H); 7.03 (s, 1H); 7.05 (s, 2H); 7.15 (t, 1H); 11.8 (s br, 1H).

MS-ESI: 573 [M+H]⁺

The starting material FR was prepared as follows:—

This preparation was exactly analogous to that of Examples 4 and 8

Yields and data are given in the following table:— Compound Yield MS-ESI RMN Fb 85% 440[M+H]⁺ ¹H NMR spectrum(CDCl₃): 1.19(d, 3H); 1.36(s, 3H); 1.41(s, 3H); 1.65(m, 6H); 1.83(m, 2H); 1.94(s, 1H); 2.23(m, 1H); 2.35(s, 6H); 3.01(m, 1H); 3.42(m, 2H); 3.69(m, 1H); 3.78(m, 1H); 4.11(m, 1H); 4.21(m, 1H); 4.41(m, 1H); 7.03(s, 1H); 7.05(s, 2H); 8.9(s br 1H). Fc 100%  540[M+H]⁺ ¹H NMR spectrum(CDCl₃): 1.06(d, 3H); 1.19(s, 9H); 1.36(s, 3H); 1.42(s, 3H); 1.56(m, 6H); 1.83(m, 2H); 1.94(s, 1H); 2.25(m, 1H); 2.35(s, 6H); 2.59(m, 1H); 3.41(m, 2H); 3.57(m, 1H); 3.67(m, 1H); 4.11(m, 1H); 4.30(m, 1H); 4.60(m, 1H); 6.84(s, 2H); 7.00(s, 1H). Fd 85% 439[M+H]⁺ ¹H NMR spectrum(DMSO d₆): 1.16(d, 3H); 1.27(s, 6H); 1.56(m, 4H); 1.68(m, 4H); 1.87(s, 1H); 2.31(s, 6H); 2.36(m, 2H); 2.72(m, 1H); 4.15(m, 3H); 7.02(s, 1H); 7.07(s, 2H); 8.9(s br 1H). FR 67% 669[M+H]⁺ ¹H NMR spectrum(DMSO d₆): 1.10(d, 3H); 1.25(s, 6H); 1.52(m, 4H); 1.67(m, 4H); 1.83(s, 1H); 2.29(s, 6H); 2.83(m, 1H); 3.19(m, 2H); 4.13(m, 3H); 6.96(s, 2H); 6.98(s, 1H); 8.12(d, 1H); 8.51(br s, 1H); 8.52(q, 1H); 8.79(d, 1H); 11.9(s br 1H).

A solution of Fd (1.12 g; 2.55 mmol) in CH₂Cl₂ (50 ml) was cooled to 0° C. under argon. DIEA (580 μl; 3.3 mmol) was added followed by a solution of DNOSCl (0.72 g; 2.68 mmol) in CH₂Cl₂ (10 ml). The mixture was allowed to warm to room temperature for 2 h and was treated with aq. HCl (1N). The mixture was extracted with CH₂Cl₂ and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH₂Cl₂ (0 to 40% EtOAc) to give FR as a yellow foam (1.14 g).

Yield: 67%

¹H NMR spectrum (DMSO d₆): 1.10 (d, 3H); 1.25 (s, 6H); 1.52 (m, 4H); 1.67 (m, 4H); 1.83 (s, 1H); 2.29 (s, 6H); 2.83 (m, 1H); 3.19 (m, 2H); 4.13 (m, 3H); 6.96 (s, 2H); 6.98 (s, 1H); 8.12 (d, 1H); 8.51 (br s, 1H); 8.52 (q, 1H); 8.79 (d, 1H); 11.9 (s br 1H).

MS-ESI: 669 [M+H]⁺

Starting material Fa was prepared as follows:—

A mixture of 8 (4.0 g; 22 mmol) and oxalyl bromide (9.5 g; 44 mmol) containing one drop of DMF was heated at 50° C. for 2 h and then cooled. The excess of oxalyl bromide was evaporated and the residue azeotroped with toluene to give crude 9 which was taken up directly in CH₂Cl₂ (30 ml) and cooled to 0° C. Diisopropylethylamine (40 ml; 200 mmol) was added followed by 2.2.2-azabicyclooctane (2.95 g; 20 mmol) in CH₂Cl₂ (20 ml). The mixture was allowed to warm to room temperature overnight and was diluted with CH₂Cl₂, washed with aq. HCl (2N), aq. NaOH (1, water, brine and dried over MgSO_(4.) The residue was evaporated to give Fa as a beige solid (3.75 g).

Yield: 68%

¹H NMR spectrum (CDCl₃): 1.38 (s, 6H); 1.67 (m, 6H); 1.89 (m, 2H); 1.95 (s, 1H); 3.40 (m, 2H); 3.63 (s, 2H) 4.02 (s, 1H).

Example 7.1

The following example was prepared in a similar manner to Example 6,

The following example was prepared in a similar manner, the table shows the NRR′ group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 7 given above:—

Example 7.1

Alcohol nPrNH₂ Mass FR mg; mg; Ph₃P mg; DTAD mg; μl; mg; —NRR′ mmol mmol mmol mmol mmol Yield

300; 0.45 150; 0.9 707; 2.7 415; 1.8 265; 4.5 193; 73% Chromato. - EtOAc ¹H NMR spectrum (DMSO d₆): 1.13 (d, 3H); 1.27 (s, 6H); 1.55 (m, 4H); 1.68 (m, 4H); 1.86 (s, 1H); 2.3 (s, 6H); 2.55-2.95 (m, 7H); 3.31 (m, 2H); 4.14 (m, 3H); 5.93 (s, 2H); 6.53 (dd, 1H); 6.67 (d, 1H); 6.74 (d, 1H); 7.02 (s, 1H); 7.05 (s, 2H); 7.15 (t, 1H); 11.74 (s br, 1H). MS-ESI: 587 [M + H]⁺

Example 8 3-[2,2-dimethyl-3-oxo-3-(azabicyclo[2.2.1]heptan-7-yl)propoxy]-4-[1-(3-methoxyphenethylaminomethyl)cycloprop-1-yl]-5-(3,5-dimethylphenyl)-1H-pyrazole

Example 8 was prepared in a similar manner to Example 7, the table shows the reaction conditions and characteristics corresponding to the description of the preparation of Example 7 given above:— Alcohol nPrNH₂ Mass GR mg; mg; Ph₃P mg; DTAD mg; μl; mg; —NRR′ mmol mmol mmol mmol mmol Yield

166; 0.25 50; 0.33 393; 1.5 230; 1.0 270; 10 68; 48% Chromato. - MeOH/CH₂Cl₂ (0 to 10% MeOH) ¹H NMR spectrum (DMSO d₆) : 0.42 (m, 2H); 0.70 (m, 2H); 1.25 (s, 6H); 1.42 (m, 4H); 1.62 (m, 4H); 2.3 (s, 6H); 2.6-2.85 (m, 7H); 3.69 (s, 3H); 4.14 (s, 3H); 4.57 (s, 2H); 6.71 (m, 3H); 7.03 (s, 1H); 7.15 (t, 1H); 7.33 (s, 2H); 11.74 (s br, 1H). MS-ESI: 571 [M + H]⁺

Starting material GR was prepared as follows:—

This preparation was exactly analogous to that of examples 4 and 7

Yields and data are given in the following table:— Com- MS-ESI pound Yield [M+H]⁺ RMN Ga 46% 245 ¹H NMR spectrum(DMSO d₆): 0.47(m, 1H); 0.64(m, 1H); 0.85(m, 1H); 0.99(m, 1H); 2.35(s, 6H); 4.11(d, 1H); 4.41(d, 1H); 4.76(s, 1H); 7.36(s, 1H); 7.59(s, 2H). Gb 87% 259 ¹H NMR spectrum(DMSO d₆): 0.28(m, 2H); 0.72(m, 2H); 2.29(s, 6H); 3.5(s, 2H); 4.8(s br, 1H); 6.96(s, 1H); 7.34(s, 2H); 9.3(s br, 1H); 11.74(s br, 1H). Gc 69% 438 ¹H NMR spectrum(DMSO d₆): 0.27(m, 2H); 0.70(m, 2H); 1.27(s, 6H); 1.42(m, 4H); 1.64(m, 4H); 2.3(s, 6H); 3.43(d, 2H); 4.14(s, 2H); 4.59(s, 2H); 4.64(t, 1H); 6.99(m, 1H); 7.41(s, 2H); 11.74(s br, 1H). Gd 60% 538 ¹H NMR spectrum(DMSO d₆): 0.17(m, 2H); 0.46(m, 2H); 1.14(s, 9H); 1.29(s, 6H); 1.45(m, 4H); 1.65(m, 4H); 2.3(s, 6H); 3.31(d, 2H); 4.23(s, 2H); 4.59(m, 3H); 7.01(s, 2H); 7.04(s, 1H). Ge 65% 437 ¹H NMR spectrum(DMSO d₆): 0.35(m, 2H); 0.67(m, 2H); 1.27(s, 6H); 1.43(m, 4H); 1.64(m, 4H); 2.3(s, 6H); 2.63(d, 2H); 4.15(s, 2H); 4.58(s, 2H); 6.99(m, 1H); 7.31(s, 2H); 11.74(s br, 1H). GR 90% 667 ¹H NMR spectrum(DMSO d₆): 0.38(m, 2H); 0.8(m, 2H); 1.28(s, 6H); 1.42(m, 4H); 1.62(m, 4H); 2.3(s, 6H); 3.17(m, 2H); 4.14(s, 2H); 4.57(s, 2H); 6.98(m, 1H); 7.27(s, 2H); 7.98(d, 1H); 8.51(dd, 1H); 8.76(d, 1H); 11.74(s br, 1H).

Example 9 3-[2,2-dimethyl-3-oxo-3-(azabicyclo[2.2.1]heptan-7-yl)propoxy]-4-(4-phenylpiperidin-1-ylmethyl)-5-(3,5-dimethylphenyl)-1H-pyrazole

A mixture of 4-phenyl piperidine (98 mg; 0.6 mmol) and formaldehyde (0.32 ml; 4.0 mmol; 37 wt % aqueous solution) in water (0.2 ml) and acetic acid (0.2 ml) was stirred for 5 min and treated with HR (74 mg; 0.2 mmol). The mixture was heated at 75° C. for 2 h. The solvents were evaporated, MeOH (0.5 ml), water (0.5 ml) and ammonia in MeOH(7N) (0.6 ml) were added and the mixture stirred for a further 3 h. The solvents were evaporated and the residue was purified by preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (80% H₂O) to give Example 9 as a white solid (75 mg).

Yield: 69%

¹H NMR spectrum (DMSO d₆): 1.27 (s, 6H); 1.42 (m, 4H); 1.6 (m, 6H); 1.75 (m, 2H); 2.07 (m, 2H); 2.32 (s, 6H); 2.52 (m, 1H); 2.97 (m, 2H); 3.16 (s, 2H); 4.17 (s, 2H); 4.57 (s, 2H); 7.02 (s, 1H); 7.17 (t, 1H); 7.23 (d, 2H); 7.28 (t, 2H) 12.1 (s, 1H).

MS-ESI: 541 [M+H]⁺

The starting material HR was prepared as follows:—

A solution of 4-(3′,5′-dimethylphenyl)acetoacetate (12.36 g; 60 mmol) in EtOH (300 ml) was treated with hydrazine hydrate (5.82 ml; 120 mmol) and heated under reflux for 3 h. The EtOH was evaporated and the residue triturated with Et₂O. The precipitate was collected, washed and dried to give Ha as a white powder (9.54 g).

Yield: 85%

¹H NMR spectrum (DMSO d₆): 2.28 (s, 6H); 5.83 (s, 1H); 6.93 (s, 1H); 7.27 (s, 2H); 9.5 (s br, 1H).

MS-ESI: 189 [M+H]⁺

A mixture of Ha (3.1 g; 16.5 mmol) and Ba (5.15 g; 19.8 mmol) in DMA (40 ml) under argon was treated with K₂CO₃ (4.56 g; 33.0 mmol). The mixture was stirred and heated at 70° C. for 5 h. The mixture was poured into sat. aq. NaHCO₃, extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO₄. The solid residue was recrystallised from toluene to give BR as a pale yellow solid (2.96 g).

Yield: 49%

¹H NMR spectrum (DMSO d₆): 1.24 (s, 6H); 1.41 (m, 4H); 1.63 (m, 4H; 2.29 (s, 6H); 4.09 (s, 2H); 4.57 (s, 2H); 6.08 (s, 1H) 6.97 (s, 1H); 7.31 (s, 2H).

MS-ESI: 368 [M+H]⁺

Examples 9.1-9.12

The following examples were prepared in a similar manner to Example 9,

the table shows the R group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 9 given above:—

Example 9.1

Amine HR mg; Formaldehyde; mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

74; 0.20 0.25; 3.0 131; 0.6 White solid 65; 54% 598 [M + H]⁺ Chromato. - Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H₂O). ¹H NMR spectrum (DMSO d₆): 1.25 (s, 6H); 1.41 (m, 6H); 1.53 (m, 2H); 1.58 (m, 4H); 2.29 (s, 6H); 2.3-2.65 (m, 12H); 3.01 (s, 2H); 4.15 (s, 2H); 4.56 (s, 2H); 7.00 (s, 1H); 7.17 (m, 3H); 7.25 (m, 2H); 7.44 (s, 2H); 11.9 (s br, 1H).

Example 9.2

Amine HR mg; Formaldehyde; mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

148; 0.40 0.32; 4.0 270; 2.0 White solid 81; 39% 529 [M + H]⁺ Chromato. - Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H₂O). ¹H NMR spectrum (DMSO d₆): 1.23(s, 6H); 1.41 (m, 4H); 1.60 (m, 4H); 1.73 (m, 2H); 2.1 (s, 3H); 2.27 (s, 6H); 2.35 (m, 2H) 2.5-2.7 (m, 2H); 3.14 (s, 2H); 4.14 (s, 2H); 4.56 (s, 2H); 6.99 (s, 1H); 7.12 (m, 3H); 7.23 (m, 2H); 7.44 (s, 2H); 11.9 (s br, 1H).

Example 9.3

Amine HR mg; Formaldehyde; mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

80; 0.20 0.25; 3.0 82; 0.6 White solid 27; 26% 516 [M + H]⁺ Chromato. - Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (100 to 0% H₂O).

Example 9.4

Amine HR mg; Formaldehyde; mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

80; 0.20 0.25; 3.0 132; 0.6 White solid 26; 22% 600 [M + H]⁺ Chromato. - Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (100 to 0% H₂O).

Example 9.5

HR mg; Formaldehyde; Amine mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

80; 0.20 0.25; 3.0 97; 0.6 White solid 37; 34% 542 [M + H]⁺ Chromato.—Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (100 to 0% H₂O).

Example 9.6

HR mg; Formaldehyde; Amine mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

80; 0.20 0.25; 3.0 102; 0.6 White solid 21; 19% 549 [M + H]⁺ Chromato.—Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (100 to 0% H₂O).

Example 9.7

HR mg; Formaldehyde; Amine mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

148; 0.40 0.16; 2.0 298; 2.0 White solid nd*; nd* 543 [M + H]⁺ Chromato.—Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H₂O). ¹H NMR spectrum (DMSO d₆): 1.24 (s, 6 H); 1.42 (m, 6 H); 1.54 (m, 2 H); 1.61 (m, 4 H); 2.06 (s, 3 H); 2.25 (s, 6 H); 2.31 (m, 2 H); 2.5-2.65 (m, 2 H); 3.12 (s, 2 H); 4.16 (s, 2 H); 4.56 (s, 2 H); 6.98 (s, 1 H); 7.13 (m, 3 H); 7.22 (m, 2 H); 7.42 (s, 2 H); 11.9 (s br, 1 H).

Example 9.8

HR mg; Formaldehyde; Amine mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

148; 0.40 0.16; 2.0 298; 2.0 gum nd*; nd* 529 [M + H]⁺ Chromato.—Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H₂O). ¹H NMR spectrum (DMSO d₆): 1.24 (s, 6 H); 1.42 (m, 6 H); 1.57 (m, 6 H); 2.28 (s, 6 H); 2.5-2.6 (m, 4 H); 3.45 (s, 2 H); 4.16 (s, 2 H); 4.55 (s, 2 H); 6.99 (s, 1 H); 7.14 (m, 3 H); 7.25 (m, 2 H); 7.30 (s, 2 H); 11.9 (s br, 1 H).

Example 9.9

HR mg; Formaldehyde; Amine mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

74; 0.20 0.08; 1.0 253; 1.0 gum 26; 24% 543 [M + H]⁺ Chromato.—Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (80% H₂O). ¹H NMR spectrum (DMSO d₆): 1.24 (s, 6 H); 1.29 (m, 2 H); 1.42 (m, 6 H); 1.53 (m, 2 H); 1.57 (m, 4 H); 2.29 (s, 6 H); 2.5-2.6 (m, 4 H); 3.46 (s, 2 H); 4.16 (s, 2 H); 4.56 (s, 2 H); 7.01 (s, 1 H); 7.15 (m, 3 H); 7.25 (m, 2 H); 7.30 (s, 2 H); 11.9 (s br, 1 H).

Example 9.10

HR mg; Formaldehyde; Amine mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

74; 0.20 0.08; 1.0 162; 1.2 White solid 42; 20% 529 [M + H]⁺ Chromato.—Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (80% H₂O). ¹H NMR spectrum (DMSO d₆): 1.24 (s, 6 H); 1.41 (m, 4 H); 1.59 (m, 4 H); 1.69 (m, 2 H); 2.29 (s, 6 H); 2.3-2.65 (m, 4 H); 3.45 (s, 2 H); 4.16 (s, 2 H); 4.56 (s, 2 H); 7.01 (s, 1 H); 7.157 (m, 3 H); 7.23 (m, 2 H); 7.31 (s, 2 H); 11.9 (s br, 1 H).

Example 9.11

HR mg; Formaldehyde; Amine mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

74; 0.20 0.08; 1.0 232; 1.2 gum 47; 41% 573 [M + H]⁺ Chromato.—Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H₂O). ¹H NMR spectrum (DMSO d₆): 1.24 (s, 6 H); 1.28 (m, 2 H); 1.41 (m, 6 H); 1.49 (m, 2 H); 1.60 (m, 4 H); 2.30 (s, 6 H); 2.3-2.65 (m, xH); 3.44 (s, 2 H); 3.70 (s, 3 H); 4.16 (s, 2 H); 4.56 (s, 2 H); 6.81 (d, 2 H); 7.01 (s, 1 H); 7.04 (d, 2 H); 7.30 (m, 2 H); 11.9 (s br, 1 H).

Example 9.12

HR mg; Formaldehyde; Amine mg; Prod. Mass mg; MS- R mmol ml; mmol mmol Form Yield ESI

74; 0.20 0.08; 3.0 97; 0.6 White solid 74; 69% 541 [M + H]⁺ Chromato.—Preparative LC/MS chromatography with H₂O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H₂O). ¹H NMR spectrum (DMSO d₆): 1.34 (m, 6 H); 1.45 (m, 5 H); 1.75 (m, 4 H); 1.9 (m, 1 H); 2.31 (m, 1 H); 2.35 (s, 6 H); 2.5 (m, 1 H); 2.59 (m, 2 H); 2.68 (m, 3 H); 3.39 (dd, 2 H); 4.28 (s, 2 H); 4.65 (s, 2 H); 7.02 (s, 1 H); 7.16 (m, 3 H); 7.25 (m, 2 H); 7.34 (s, 2 H); 8.9 (s br, 1 H).

Example 10 2-[3-(2,2-dimethyl-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine

A solution of Example 4 (123 mg; 0.21 mmol) in THF (3 ml) under argon was treated with a solution of LiAlH₄ (420 μl; 0.42 mmol; 1M solution in THF). The mixture was heated at 60° C. for 1 h. The mixture was treated with an excess of Glaubers' Salt (Na₂SO₄. 10H₂O), filtered and evaporated. The residue was purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH₂Cl₂ (5 to 15% MeOH) to give Example 10 as a white solid (80 mg).

Yield: 68%

¹H NMR spectrum (DMSO d₆): 0.93 (s, 6H); 1.18 (d, 3H); 1.2 (m, 4H); 1.59 (m, 4H); 2.19 (s, 2H); 2.3 (s, 6H); 2.55-2.95 (m, 7H); 3.07 (s, 2H); 3.86 (s, 2H); 5.94 (s, 2H); 6.53 (d, 1H); 6.66 (s, 1H); 6.74 (d, 1H); 7.04 (s, 1H); 7.05 (s, 2H); 11.7 (s br 1H).

MS-ESI: 559 [M+H]⁺

Example 11 2-[3-(2,2-dimethyl-3-hydroxypropoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine

A solution of JR (109 mg; 0.17 mmol) in THF (2 ml) under argon was treated with a solution of LiAlH₄ (350 ul; 0.35 mmol; 1M solution in THF). The mixture was heated at 60° C. for 1 h. The mixture was treated with an excess of Glaubers Salt (Na₂SO₄.10H₂O), filtered and evaporated. The residue was purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH₂Cl₂ (0 to 15% MeOH) to give Example 11 as a white solid (68 mg).

Yield: 84%

¹H NMR spectrum (DMSO d₆): 0.92 (s, 6H); 1.17 (d, 3H); 2.3 (s, 6H); 2.5-2.9 (m, 7H); 3.27 (s, 2H); 3.86 (s, 2H); 4.61 (t br, 1H); 5.94 (s, 2H); 6.53 (d, 1H); 6.67 (s, 1H); 6.74 (d, 1H); 7.03 (s, 1H); 7.04 (s, 2H); 11.7 (s br 1H).

MS-ESI: 480 [M+H]⁺

Starting material JR was prepared as follows:—

A solution of Example 4 (205 mg; 0.35 mmol) in acetonitrile (2 ml) was treated with c.HCl (1 ml) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated, extrated with CH₂Cl₂ and the organic phase was washed with water, brine and dried over MgSO₄. The residue a was obtained as a yellow solid (218 mg). It was used directly in the final step of the synthesis of Example 11.

Yield: 80%

¹H NMR spectrum (DMSO 4): 1.24 (m, 9H); 2.33 (s, 6H); 2.78 (m, 2H); 2.95 (m, 2H); 3.14 (m, 3H); 4.13 (m, 2H); 5.98 (s, 2H); 6.62 (d, 1H); 6.76 (s, 1H); 6.84 (d, 1H); 7.05 (s, 2H); 7.07 (s, 2H); 8.6 (s br, 1H); 11.7 (s br 1H).

MS-ESI: 494 [M+H]⁺

Example 12 2-[3-(2,2-dimethyl-3-oxo3-isopropoxy-propoxy)-5-(3,5-ditnethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine

A solution of JR (109 mg; 0.17 mmol) in CH₂Cl₂ (1 ml) was added to a solution of EDCl (37 mg; 0.19 mmol) and DMAP (5 mg; cat.) in iPrOH (5 ml). H₂SO₄ (5 drops; cat.) was added and the mixture was heated under reflux overnight over molecular sieves. The mixture was concentrated and extracted with CH₂Cl₂/water and the organic phase was washed with water, brine and dried over MgSO₄. The residue was purified by flash chromatography eluting with increasingly polar mixtures of MeOH(CH₂Cl₂ (0 to 10% MeOH) to give Example 12 as a yellow gum (59 mg).

Yield: 65%

¹H NMR spectrum (DMSO d₆): 1.16 (m, 6H); 1.24 (m, 9H); 2.32 (s, 6H); 2.8 (m, 2H); 2.95 (m, 2H); 3.15 (m, 3H); 4.16 (dd, 2H); 4.88 (m, 1H); 5.98 (s, 2H); 6.62 (d, 1H); 6.74 (s, 1H); 6.83 (d, 1H); 7.04 (s, 2H); 7.07 (s, 2H); 11.7 (s br 1H).

MS-ESI: 536 [M+H]⁺

Therapeutic Uses

Compounds of Formula (I) are provided as medicaments for antagonising gonadotropin releasing hormone (GnRH) activity in a patient, eg, in men and/or women. To this end, a compound of Formula (I) can be provided as part of a pharmaceutical formulation which also includes a pharmaceutically acceptable diluent or carrier (eg, water). The formulation may be in the form of tablets, capsules, granules, powders, syrups, emulsions (eg, lipid emulsions), suppositories, ointments, creams, drops, suspensions (eg, aqueous or oily suspensions) or solutions (eg, aqueous or oily solutions). If desired, the formulation may include one or more additional substances independently selected from stabilising agents, wetting agents, emulsifying agents, buffers, lactose, sialic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter and ethylene glycol.

The compound is preferably orally administered to a patient, but other routes of administration are possible, such as parenteral or rectal administration. For intravenous, subcutaneous or intramuscular administration, the patient may receive a daily dose of 0.1 mgkg⁻¹ to 30 mgkg⁻¹ (preferably, 5 mgkg⁻¹ to 20 mgkg⁻¹) of the compound, the compound being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively, the intravenous dose may be given by continuous infusion over a period of time. Alternatively, the patient may receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day. A suitable pharmaceutical formulation is one suitable for oral administration in unit dosage form, for example as a tablet or capsule, which contains between 10 mg and 1 g (preferably, 100 mg and 1 g) of the compound of the invention.

Buffers, pharmaceutically acceptable co-solvents (eg, polyethylene glycol, propylene glycol, glycerol or EtOH) or complexing agents such as hydroxy-propyl β cyclodextrin may be used to aid formulation.

One aspect of the invention relates to the use of compounds according to the invention for reducing the secretion of LH and/or FSH by the pituitary gland of a patient. In this respect, the reduction may be by way of a reduction in biosynthesis of the LH and FSH and/or a reduction in the release of LH and FSH by the pituitary gland. Thus, compounds according to the invention can be used for therapeutically treating and/or preventing a sex hormone related condition in the patient. By “preventing” we mean reducing the patient's risk of contracting the condition. By “treating” we mean eradicating the condition or reducing its severity in the patient. Examples of sex hormone related conditions are: a sex hormone dependent cancer, benign prostatic hypertrophy, myoma of the uterus, endometriosis, polycystic ovarian disease, uterine fibroids, prostatauxe, myoma uteri, hirsutism and precocious puberty. Examples of sex hormone dependent cancers are: prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenoma.

The compounds of the invention may be used in combination with other drugs and therapies used to treat/prevent sex-hormone related conditions.

If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically-active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate.

In the field of medical oncology examples of such combinations include combinations with the following categories of therapeutic agent:

i) anti-angiogenic agents (for example linomide, inhibitors of integrin αvβ3 function, angiostatin, endostatin, razoxin, thalidomide) and including vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors (RTKIs) (for example those described in international patent applications publication nos. WO-97/22596, WO-97/30035, WO-97/32856 and WO-98/13354, the entire disclosure of which documents is incorporated herein by reference);

ii) cytostatic agents such as anti-oestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrozole, vorazole, exemestane), anti-progestogens, anti-androgens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), inhibitors of testosterone 5α-dihydroreductase (for example finasteride), anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of uroidnase plasminogen activator receptor function) and inhibitors of growth factor function, (such growth factors include for example epidermal growth factor (EGF), platelet derived growth factor and hepatocyte growth factor such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors);

iii) biological response modifiers (for example interferon);

iv) antibodies (for example edrecolomab); and

v) anti-proliferative/anti-neoplastic drugs and combinations thereof, as used in medical oncology, such as anti-metabolites (for example anti-folates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); anti-tumour antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); anti-mitotic agents (for example vinca alkaloids like vincristine and taxoids like taxol, taxotere); enzymes (for example asparaginase); thymidylate synthase inhibitors (for example raltitrexed); topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, irinotecan).

The compounds of the invention may also be used in combination with surgery or radiotherapy.

Assays

The ability of compounds according to the invention to act as antagonists of GnRH can be determined using the following in vitro assays.

Binding Assay Using Rat Pituitary GnRH Receptor

The assay is performed as follows:—

-   1. Incubate crude plasma membranes prepared from rat pituitary     tissues in a Tris.HCl buffer (pH. 7.5, 50 mM) containing bovine     serum albumin (0.1%), [I-125]D-t-Bu-Ser6-Pro9-ethyl amide-GnRH, and     the test compound. Incubation is at 4° C. for 90 minutes to 2 hours. -   2. Rapidly filter and repeatedly wash through a glass fibre filter. -   3. Determine the radioactivity of membrane bound radio-ligands using     a gamma counter.

From this data, the IC₅₀ of the test compound can be determined as the concentration of the compound required to inhibit radio-ligand binding to GnRH receptors by 50%.

Compounds according to the present invention have activity at a concentration from 1 nM to 5 μM.

Binding Assay Using Human GnRH Receptor

Crude membranes prepared from CHO cells expressing human GnRH receptors are sources for the GnRH receptor. The binding activity of compounds according to the invention can be determined as an IC₅₀ which is the compound concentration required to inhibit the specific binding of [¹²⁵I]buserelin to GnRH receptors by 50%. [¹²⁵I]Buserelin (a peptide GnRH analogue) is used here as a radiolabelled ligand of the receptor.

Assay to Determine Inhibition of LH Release

The LH release assay can be used to demonstrate antagonist activity of compounds, as demonstrated by a reduction in GnRH-induced LH release.

Preparation of Pituitary Glands

Pituitary glands obtained from rats are prepared as follows. Suitable rats are Wistar male rats (150-200 g) which have been maintained at a constant temperature (eg, 25° C.) on a 12 hour light/12 hour dark cycle. The rats are sacrificed by decapitation before the pituitary glands are aseptically removed to tube containing Hank's Balanced Salt Solution (HBSS).

The glands are further processed by:—

-   1. Centrifugation at 250×g for 5 minutes; -   2. Aspiration of the HBSS solution; -   3. Transfer of the glands to a petri dish before mincing with a     scalpel; -   4. Transfer of the minced tissue to a centrifuge tube by suspending     the tissue three successive times in 10 ml aliquots of IBSS     containing 0.2% collagenase and 0.2% hyaluronidase; -   5. Cell dispersion by gentle stirring of the tissue suspension while     the tube is kept in a water bath at 37° C.; -   6. Aspiration 20 to 30 times using a pipette, undigested pituitary     fragments being allowed to settle for 3 to 5 minutes; -   7. Aspiration of the suspended cells followed by centrifugation at     1200×g for 5 minutes; -   8. Re-suspension of the cells in culture medium of DMEM containing     0.37% NaHCO₃, 10% horse serum, 2.5% foetal bovine serum, 1% non     essential amino acids, 1% glutamine and 0.1% gentamycin; -   9. Treatment of the undigested pituitary fragments 3 times with 30     ml aliquots of the collagenase and hyaluronidase; -   10. Pooling of the cell suspensions and dilution to a concentration     of 3×10⁵ cells/ml; -   11. Placing of 1.0 ml of this suspension in each of a 24 well tray,     with the cells being maintained in a humidified 5% CO₂/95% air     atmosphere at 37° C. for 3 to 4 days     Testing of Compounds

The test compound is dissolved in DMSO to a final concentration of 0.5% in the incubation medium.

1.5 hours prior to the assay, the cells are washed three times with DMEM containing 0.37% NaHCO₃, 10% horse serum, 2.5% foetal bovine serum, 1% non essential amino acids (100×), 1% glutamine (100×), 1% penicillin/streptomycin (10,000 units of each per ml) and 25 mM HEPES at pH 7.4. Immediately prior to the assay, the cells are again washed twice in this medium.

Following this, 1 ml of fresh medium containing the test compound and 2 nM GnRH is added to two wells. For other test compounds (where it is desired to test more than one compound), these are added to other respective duplicate wells. Incubation is then carried out at 37° C. for three hours.

Following incubation, each well is analysed by removing the medium from the well and centrifuging the medium at 2000×g for 15 minutes to remove any cellular material. The supernatant is removed and assayed for LH content using a double antibody radio-immuno assay. Comparison with a suitable control (no test compound) is used to determine whether the test compound reduces LH release. Compounds according to the present invention have activity at a concentration from 1 nM to 5 μM. 

1. A compound of Formula (I),

wherein R¹ is selected from: hydrogen, optionally-substituted C₁₋₆alkyl, optionally substituted aryl or optionally-substituted arylC₁₋₆alkyl; R² is an optionally-substituted mono or bi-cyclic aromatic ring; R³ is selected from a group of Formula (IIa) to Formula (IIf):

R⁵ is a group of Formula (III):

R⁶ and R^(6a) are independently selected from hydrogen, fluoro, optionally substituted C₁₋₆alkyl, optionally-substituted aryl or optionally substituted arylC₁₋₆alkyl, or R⁶ and R^(6a) taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms, or R⁶ and R^(6a) taken together and the carbon atom to which they are attached form a carbonyl group; or when A is not a direct bond the group

 forms a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms; or the group

 forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; R⁷ is selected from: hydrogen, optionally-substituted C₁₋₆alkyl, optionally-substituted arylC₁₋₆alkyl, optionally-substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylC₁₋₆alkyl, R⁹OC₁₋₆alkyl-, R⁹R¹⁰NC₁₋₆alkyl-, R⁹R¹⁰NC(O)C₁₋₆alkyl, —C(NR⁹R¹⁰)═NH; or when R³ is a group of Formula (IIc) or (IId) R⁷ is of the formula -J-K—R⁸; R⁸ is selected from: (i) hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, haloC₁₋₆alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxy, hydroxyC₁₋₆alkyl, cyano, N—C₁₋₄alkylamino, N,N-di-C₁₋₄alkylamino, C₁₋₆alkyl-S(O_(n))—, —O—R^(b), —NR^(b)R^(c), —(O)—R^(b), —C(O)O—R^(b), —CONR^(b)R^(c), NH—C(O)—R^(b) or —S(O_(n))NR^(b)R^(c), where R^(b) and R^(c) are independently selected from hydrogen and C₁₋₄alkyl optionally substituted with hydroxy, amino, N—C₁₋₄alkylamino, N,N-di-C₁₋₄alkylamino, HO—C₂₋₄alkyl-NH— or HO—C₂₋₄alkyl-N(C₁₋₄alkyl)-; (ii) nitro when B is a group of Formula (IV) and X is CH and p is 0; (iii) C₃₋₇cycloalkyl, aryl or arylC₁₋₆alkyl each of which is optionally substituted by R², R¹³ and R¹⁴; (iv) -(Q)-aryl, -(Q)-heterocyclyl, -aryl-(Q)-aryl, each of which is optionally substituted by R¹², R¹³ and R¹⁴ wherein -(Q)- is selected from E, F or a direct bond; (v) heterocyclyl or heterocyclylC₁₋₆alkyl each of which is optionally substituted by up to 4 substituents independently selected from R¹², R¹³ and R¹⁴; (vi) a group selected from R¹², R¹³ and R¹⁴; R⁹ and R¹⁰ are independently selected from: hydrogen, hydroxy, optionally substituted C₁₋₆alkyl, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl, an optionally substituted carbocyclic ring of 3-7 atoms, optionally substituted heterocyclyl, optionally substituted heterocyclylC₁₋₆alkyl or R⁹ and R¹⁰ taken together can form an optionally substituted ring of 3-9 atoms or R⁹ and R¹⁰ taken together with the carbon atom to which they are attached form a carbonyl group; R¹¹ is selected from: hydrogen, optionally substituted C₁₋₆alkyl, or N(R⁹R¹⁰); R¹² is selected from: hydrogen, hydroxy, R¹⁷R¹⁸N(CH₂)_(cc)—, R¹⁷R¹⁸NC(O)(CH₂)_(cc)—, optionally substituted C₁₋₆alkyl-C(O)N(R⁹)(CH₂)_(cc)—, optionally substituted C₁₋₆alkyl-SO₂N(R⁹)—, optionally substituted aryl-SO₂N(R⁹)—, C₁₋₃perfluoroalkyl-SO₂N(R⁹)—; optionally substituted C₁₋₆alkyl-N(R⁹)SO₂—, optionally substituted aryl-N(R⁹)SO₂—, C₁₋₃perfluoroalkyl-N(R⁹)SO₂— optionally substituted C₁₋₆alkanoyl-N(R⁹)SO₂—; optionally substituted aryl-C(O)N(R⁹)SO₂—, optionally substituted C₁₋₆alkyl-S(O_(n))—, optionally substituted aryl-S(O_(n))—, C₁₋₃perfluoroalkyl-, C₁₋₃perfluoroalkoxy, optionally substituted C₁₋₆alkoxy, carboxy, halo, nitro or cyano; R¹³ and R¹⁴ are independently selected from: hydrogen, hydroxy, oxo, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆alkanoyl, optionally substituted C₂₋₆alkenyl, cyano, nitro, C₁₋₃perfluoroalkyl-, C₁₋₃perfluoroalkoxy, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl, R⁹O(CH₂)_(s)—, R⁹(O)O(CH₂)_(s)—, R⁹OC(O)(CH₂)_(s)—, R¹⁶S(O_(n))(CH₂)_(s)—, R⁹R¹⁰NC(O)(CH₂)_(s)— or halo; R¹⁵ is selected from: hydrogen, optionally substituted C₁₋₆alkyl, R¹⁹OC(O)—, R⁹R¹⁰NC(O)—, R⁹C(O)—, R⁹S(O_(n))—; R¹⁶ is selected from: hydrogen, C₁₋₆alkyl, C₁₋₃perfluoroalkyl or optionally-substituted aryl; R¹⁷ is independently selected from: hydrogen, hydroxy, cyano or optionally substituted C₁₋₆alkyl; R¹⁸ is a group of formula R^(18a)—C(R⁹R¹⁰)₀₋₁— wherein R^(18a) is selected from: R¹⁹OC(O)—, R⁹R¹⁰NC(O)—, R⁹R¹⁰N—, R⁹C(O)—, R⁹C(O)N(R¹⁰)—, R⁹R¹⁰NC(O)—, R⁹R¹⁰NC(O)N(R¹⁰)—, R⁹SO₂N(R¹⁰)—, R⁹R¹⁰NSO₂N(R¹⁰)—, R⁹C(O)O—, R⁹OC(O)—, R⁹R¹⁰NC(O)O—, R⁹O—, R⁹S(O_(n))—, R⁹R¹⁰NS(O_(n))—, hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted heterocyclyl; or R¹⁷ and R¹⁸ when taken together form an optionally substituted carbocyclic ring of 3-7 atoms or optionally substituted heterocyclyl; R¹⁹ is selected from: hydrogen, optionally substituted C₁₋₆alky, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl, optionally substituted C₃₋₇cycloalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylC₁₋₆alkyl; R²⁰ is selected from R¹² or R¹³; R²¹ and R²² are independently selected from hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₇cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC₁₋₆alkyl, optionally substituted C₃₋₆alkenyl, optionally substituted C₃₋₆alkynyl, —(C₁₋₅alkyl)_(aa)-S(O_(n))—(C₁₋₅alkyl)_(bb)-; R⁹R¹⁰NC₂₋₆alkyl, R⁹OC₂₋₆alkyl or R⁹R¹⁰NC(O)C₂₋₆alkyl, with the proviso that R⁹ and R¹⁰ independently or taken together are not optionally substituted aryl or optionally substituted arylC₁₋₆alkyl; or R²¹ and R²² taken together form an optionally substituted non-aromatic heterocyclic ring; A is selected from: (i) a direct bond; (ii) optionally-substituted C₁₋₅alkylene wherein the optional substituents are independently selected from: optionally-substituted C₁₋₆alkyl optionally-substituted aryl, optionally substituted arylC₁₋₆alkyl or substituted arylC₁₋₆alkyl; (iii) a carbocyclic ring of 3-7 atoms; (iv) a carbonyl group or —C(O)—C(R^(d)R^(d))—, wherein R^(d) is independently selected from hydrogen and C₁₋₂alkyl; or when R³ is a group of Formula (IIa) or (IIb), the group

 forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; or when R³ is a group of Formula (IIa), (IIb), (IIc) or (IId), the group

 forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; B is selected from: (i) a direct bond; (ii) a group of Formula (IV)

wherein: X is selected from N or CH, wherein at position (a) Formula (IV) is attached to the nitrogen atom and the (CH₂)p group is attached to R⁸; and (iii) a group independently selected from: optionally substituted C₁₋₆alkylene, optionally substitute C₃₋₇cycloalkyl, optionally substituted C₃₋₆alkenylene, optionally substituted C₃₋₆alkynyl, C₁₋₆alkoxy, (C₁₋₅alkyl)_(aa)-S(O_(n))—(C₁₋₅alkyl)_(bb)-, (C₁₋₅alkyl)_(aa)-O—(C₁₋₅alkyl)_(bb)-, —(C₁₋₅alkyl)_(aa)-C(O)—(C₁₋₅alkyl)_(bb)- or (C₁₋₅alkyl)_(aa)-N(R¹⁵)—(C₁₋₅alkyl)_(bb), wherein R¹⁵ and the (C₁₋₅alkyl)_(aa) or (C₁₋₅alkyl)_(bb) chain can be joined to form a ring, wherein the combined length of (C₁₋₅alkyl)_(aa) and (C₁₋₅alkyl)_(bb) is less than or equal to C₅alkyl; or the group —B—R⁸ represents a group of Formula (V)

or the group

 together forms an optionally substituted heterocylic ring containing 4-7 carbons atoms; or the group

 forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; E is —O—, —S(O_(n)), —C(O)—, —NR¹⁵— or —C(R⁹R¹⁰)_(q); F is -E(CH₂)_(r)—; G is selected from: hydrogen, halo, N, O, S(O_(n)), C(O), C(R⁹R¹⁰)_(t), optionally substituted C₂₋₆alkenylene, optionally substituted C₂₋₆alkynylene or a direct bond to R¹⁸, J is a group of the formula: —(CH₂)_(s)-L-(CH₂)_(s)— wherein when s is greater than 0, the alkylene group is optionally substituted, or the group

 together forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms; K is selected from: a direct bond, —(CH₂)_(s1)—, —(CH₂)_(s1)—O—(CH₂)_(s2)—, —(CH₂)_(s1)C(O)—(CH₂)_(s2)—, —(CH₂)_(s1)S(O_(n))—(CH₂)_(s2)—, —(CH₂)_(s1)N(R¹⁸)—(CH₂)_(s2)—, —(CH₂)_(s1)—C(O)N(R⁹)—(CH₂)_(s2)—, —(CH₂)_(s1)—N(R⁹)C(O)—(CH₂)_(s2)—, —(CH₂)_(s1)—N(R⁹)C(O)N(R⁹)—(CH₂)_(s2)—, —(CH₂)_(s1)—OC(O)—(CH₂)_(s2)—, —(CH₂)_(s1)—C(O)O—(CH₂)_(s2)—, —(CH₂)_(s1)—N(R⁹)C(O)O—(CH₂)_(s2)—, —(CH₂)_(s1)—OC(O)N(R⁹)—(CH₂)_(s2)—, —(CH₂)_(s1)—OS(O_(n))—(CH₂)_(s2)—, or —(CH₂)_(s1)—S(O_(n))—O—(CH₂)_(s2)—(CH₂)_(s1)—S(O)₂N(R⁹)—(CH₂)_(s2)—, —(CH₂)_(s1)—N(R⁹)S(O)₂—(CH₂)_(s2)—; wherein the —(CH₂)_(s1)— and —(CH₂)_(s2)— groups are independently optionally substituted by hydroxy or C₁₋₄alkyl; L is selected from optionally substituted aryl or optionally substituted heterocyclyl; M is selected from —(CH₂)₀₋₂—O— or —C(O)NH—; n is an integer from 0 to 2; p is an integer from 0 to 4; q is an integer from 0 to 4; r is an integer from 0 to 4; s is an integer from 0 to 4; s1 and s2 are independently selected from an integer from 0 to 4, and s1+s2 is less than or equal to 4; t is an integer from 0 to 4; aa and bb, are independently 0 or 1; and cc is an integer between 0 to 2; with the proviso that (i) when G is hydrogen or halo, then R¹⁷ and R¹⁸ are both absent; (ii) when G is O, S(O_(n)), C(O) or C(R¹¹R¹²)_(t) then G is substituted by a single group independently selected from the definition of R¹⁷ or R¹⁸ and when G is a direct bond to R¹⁸ then G is substituted by a single group selected from R¹⁸; and (iii) when R³ is a group of Formula (IIb), B is a group of Formula (IV), R⁸ is selected from group (i) or (ii) above, R¹¹ is a group of the formula N(R¹⁰R¹¹) and R¹, R² and R⁵ are as defined above then R⁴ cannot be hydrogen; or a salt, pro-drug or solvate thereof.
 2. A compound according to claim 1 wherein R¹ is hydrogen.
 3. A compound according to claim 1 wherein R³ is selected from a group of Formula (IIa) or Formula (IIb).
 4. A compound according to claim 3 wherein B is optionally substituted C₁₋₆alkylene.
 5. A compound according to claim 1 wherein R³ is selected from a group of Formula (IIc) or Formula (IId).
 6. A compound according to claim 5 wherein the group

together forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms
 7. A compound according to claim 6 wherein K is selected from: —(CH₂)_(s)—, —(CH₂)_(s)—O—(CH₂)_(s)—, —(CH₂)_(s)—C(O)—(CH₂)_(s)—, —(CH₂)_(s)—N(R¹⁸)—(CH₂)_(s)—, —(CH₂)_(s)—C(O)N(R¹⁸)—(CH₂)_(s)—, —(CH₂)_(s)—N(R⁸)C(O)—(CH₂)_(s)—, —(CH₂)_(s)—S(O)₂N(R¹⁸)—(CH₂)_(s)—, or —(CH₂)_(s)—NHS(O)₂—(CH₂)_(s)—.
 8. A compound according to claim 3 wherein R⁸ is selected from: (i) hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, haloC₁₋₆-alkyl, hydroxy, cyano, C₁₋₆alkylS(O_(n))—, —O—R^(b), C₁₋₄alkoxyC₁₋₄alkyl, —C(O)—R^(b), C(O)O—R^(b), —NH—C(O)—R^(b), N,N-di-C₁₋₄alkylamino, —S(O_(n))NR^(b)R^(c) where R^(b) and R^(c) are independently selected from hydrogen and C₁₋₆alkyl, and n is 0, 1 or 2; (ii) -(Q)-aryl, optionally substituted by up to 3 groups selected from R¹², R¹³ and R¹⁴; (iii) C₄₋₇ heterocyclyl, optionally substituted by up to 3 groups selected from R¹², R¹³ and R¹⁴, or (iv) C₃₋₇carbocyclyl, optionally substituted by up to 3 groups selected from R¹², R¹³ and R¹⁴;
 9. A compound according to claim 1 wherein R⁵ is a group of Formula (III) wherein the group of Formula (III) is selected from any one of III-a to III-l;

wherein: het represents an optionally substituted 3- to 8-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N and S; R²³ and R^(23a) are independently selected from hydrogen, fluoro or optionally substituted C₁₋₈alkyl; or R²³ and R^(23a) together with the carbon to which they are attached form an optionally substituted 3 to 7-membered cycloalkyl ring R²⁴ is selected from hydrogen, optionally substituted C₁₋₈alkyl, optionally substituted aryl, —R^(d)—Ar, where R^(d) represents C₁₋₈alkylene and Ar represents optionally substituted aryl, and optionally substituted 3- to 8-membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; R²⁵ is selected from hydrogen; optionally substituted C₁₋₈alkyl and optionally substituted aryl; or where the group of Formula (III) represents a group of Formula III-a, III-b or III-i, then the group NR²⁴(—R²⁵) represents an optionally substituted 3- to 8-membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; or where the group of Formula (III) represents structure III-e, R²⁴ and R²⁵ together with the carbon to which they are attached represents an optionally substituted 3- to 8-membered heterocyclic ring optionally containing from 1 to 4 heteroatoms independently selected from O, N and S;
 10. A compound according to claim 1 wherein R² is selected from an optionally substituted monocyclic aromatic ring structure wherein the optional substituents are selected from cyano, NR^(e)R^(f), optionally substituted C₁₋₈alkyl, optionally substituted C₁₋₈alkoxy or halo wherein R^(e) and R^(f) are independently selected from hydrogen, C₁₋₆alkyl or aryl.
 11. A compound selected from: 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-pyrid-4-ylethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-pyrid-4-ylbutyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[4-(4-methoxyphenyl)butyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(43-trifluoromethylphenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-fluorophenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(3-methoxyphenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-methoxyphenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(4-methylsulphonylaminophenyl)ethyl]-(2S)-propylamine; and 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.2]oct-2-yl}propoxy)-5-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]-N-[2-(1,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine; or a salt, pro-drug or solvate thereof.
 12. (canceled)
 13. A pharmaceutical formulation comprising a compound, or salt, pro-drug or solvate thereof, according to claim 1 and a pharmaceutically acceptable diluent or carrier.
 14. A method of antagonising gonadotropin releasing hormone activity in a patient the method comprising administering a compound, or salt, pro-drug or solvate thereof, according to claim 1 to a patient.
 15. A method of treating and/or preventing a sex hormone related condition in a patient, the method comprising administering a compound according to claim 1, or salt, pro-drug or solvate thereof, to a patient.
 16. A process for the preparation of a compound of Formula (I) as defined in claim 1, comprising a process selected from (a) to (h) as follows: (a) Reaction of a compound of formula XXXII with a compound of formula H—R⁵′ to form a compound of Formula (I),

 wherein X¹ is selected from:

 is a displaceable group; and H—R⁵′ is selected from:

(b) Reaction of a compound of formula XXXIII with a compound of formula H—R⁵″ to form a compound of Formula (I),

wherein X² is selected from:

 L² is a displaceable group and R^(7a) is selected from the definition of R⁷ or R²² above, and L²-R⁵″ is selected from: L²-B—R⁸, L²-J-K—R⁸ and L²-R²¹ (c) For compounds of Formula (I) wherein R³ is a group of Formula (IIa), (IIb), (IIc) or (IId) and R⁷ is other than part of a heterocyclic ring or hydrogen, reaction of a compound of Formula (I) wherein R³ is a group of Formula (IIa), (IIb), (IIc) or (IId) and R⁷ is hydrogen with a group of formula L³-R^(7a), wherein R^(7a) is as defined above for R⁷ with the exclusion of hydrogen and L³ is a displaceable group; (d) For compounds of Formula (I) wherein R³ is a group of Formula (IIe) or (IIf) and R²¹ is other than hydrogen, reaction of a compound of Formula (I) wherein R³ is a group of Formula (IIe) or (IIf) and R²¹ is hydrogen with a group of formula L⁴-R^(21a), wherein R^(21a) is as defined above for R²¹ with the exclusion of hydrogen and L⁴ is a displaceable group; (e) For compounds of Formula (I) wherein R³ is a group of Formula (IIe) or (IIf) and R²² is other than hydrogen, reaction of a compound of Formula (I) wherein R³ is a group of Formula (IIe) or (IIf) and R²² is hydrogen with a group of formula L⁵-R^(22a), wherein R^(22a) is as defined above for R²² with the exclusion of hydrogen and L⁵ is a displaceable group; (f) For compounds of Formula (I) wherein R³ is a group of Formula (IIc) or (IId) and  the group

 together forms an optionally substituted nitrogen-containing heterocyclic ring containing 4-7 carbons atoms, reaction of a compound of Formula XXXIVa or XXXIVb, with a compound of Formula L⁶-K—R⁸, wherein L³ is a displaceable group

(g) For compounds of Formula (I) wherein R³ is a group of Formula (IIc) or (IId), reaction of a compound of Formula XXXVa or XXXVb, with a compound of Formula L⁷-K″—R⁸, wherein L⁷ is a displaceable group, and wherein the groups K′ and K″ comprise groups which when reacted together form K,

(h) reaction of a compound of Formula XXXVI with a compound of the formula L⁸-R⁵, wherein L⁸ is a displaceable group

 and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (I); ii) removing any protecting groups; iii) forming a salt, pro-drug or solvate. 